1,380 results
Search Results
2. Commentary on the 1962 Transfusion paper by Don Thomas and Joe Ferrebee.
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BONE marrow cells , *NOBEL Prize in Physiology or Medicine , *HEMATOPOIETIC system , *TOTAL body irradiation - Published
- 2022
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3. Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT)
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Michael T. Brennan, Barry Quinn, Jakob Passweg, Jacqui Stringer, Arno Mank, Sharon Elad, Richard M. Logan, Judith E. Raber-Durlacher, Michael Y. Shapira, C.M.J. Potting, Karin Garming-Legert, Deborah P. Saunders, Tuomas Waltimo, Monique A. Stokman, Siri Beier Jensen, Yehuda Zadik, Samuel Vokurka, M. Elvira P. Correa, Yoshihiko Soga, Göran Dahllöf, Noam Yarom, Nicole M. A. Blijlevens, Joel B. Epstein, Elisabeth Wallhult, MKA AMC (OII, ACTA), Orale Geneeskunde (OII, ACTA), Parodontologie (OII, ACTA), Faculteit der Geneeskunde, Maxillofacial Surgery (AMC), Oral Medicine, and Periodontology
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Male ,MUCOSAL COATING AGENTS ,medicine.medical_treatment ,Oral Health ,XEROSTOMIA ,Hematopoietic stem cell transplantation ,Review Article ,RECEIVING CANCER-THERAPY ,GUIDELINES ,OROFACIAL PAIN ,Clinical Protocols ,Bone Marrow ,VERSUS-HOST-DISEASE ,Health care ,Dental Care ,Cancer ,Bone Marrow Transplantation ,Nursing research ,Hematopoietic Stem Cell Transplantation ,Hygiene ,Hematology ,Oncology ,MANAGEMENT STRATEGIES ,Hematologic Neoplasms ,SALIVARY-GLAND HYPOFUNCTION ,Female ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Oral ,medicine.medical_specialty ,MEDLINE ,Bone Marrow Cells ,Oral hygiene ,Quality of life (healthcare) ,SDG 3 - Good Health and Well-being ,medicine ,Mucositis ,Humans ,Pain Management ,Intensive care medicine ,business.industry ,medicine.disease ,Oral Hygiene ,Surgery ,CLINICAL-PRACTICE ,Quality of Life ,Position paper ,Dental ,MUCOSITIS ,business - Abstract
Contains fulltext : 154632.pdf (Publisher’s version ) (Open Access) PURPOSE: Hematology-oncology patients undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT) recipients are at risk for oral complications which may cause significant morbidity and a potential risk of mortality. This emphasizes the importance of basic oral care prior to, during and following chemotherapy/HSCT. While scientific evidence is available to support some of the clinical practices used to manage the oral complications, expert opinion is needed to shape the current optimal protocols. METHODS: This position paper was developed by members of the Oral Care Study Group, Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT) in attempt to provide guidance to the health care providers managing these patient populations. RESULTS: The protocol on basic oral care outlined in this position paper is presented based on the following principles: prevention of infections, pain control, maintaining oral function, the interplay with managing oral complications of cancer treatment and improving quality of life. CONCLUSION: Using these fundamental elements, we developed a protocol to assist the health care provider and present a practical approach for basic oral care. Research is warranted to provide robust scientific evidence and to enhance this clinical protocol.
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- 2015
4. Cabbage-derived three-dimensional cellulose scaffold-induced osteogenic differentiation of stem cells.
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Salehi A, Mobarhan MA, Mohammadi J, Shahsavarani H, Shokrgozar MA, and Alipour A
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- Cell Differentiation, Cellulose, Humans, Osteogenesis physiology, Bone Marrow Cells, Brassica, Mesenchymal Stem Cells, Tissue Engineering methods, Tissue Scaffolds chemistry
- Abstract
Herbal-derived three-dimensional scaffolds have a unique structure that represents the natural cellular microenvironment and can be potentially used for tissue engineering applications. In the present study, cabbage (Cb) leaves were decellularized and then their characteristics, such as surface roughness, wettability, porosity, mechanical properties, and specific surface area, were investigated. After that, scaffold osteoinductivity was studied by bone-marrow-derived mesenchymal stem cells (BM-MSCs) osteogenic differentiation while growing on the decellularized Cb leaves. Cells mineralization, calcium secretion, alkaline phosphatase (ALP) activity, and expression levels of bone-related genes were determined during the differentiation process. Our results from the structural characterization of the scaffolds demonstrated that decellularized Cb leaves are good candidates for bone differentiation in terms of surface roughness, mechanical properties, and interconnected pores. Osteogenic differentiation evaluation of the BM-MSCs determined that the cell's ALP activity and mineralization were increased significantly while cultured on the decellularized Cb leaves compared to the cells cultured on the culture plate as a control. Besides, Runx2, ALP, collagen-1 (Col-I), and osteocalcin genes were expressed in cells cultured on decellularized Cb leaves significantly higher than cells cultured on the culture plate. Based on these results, it can be concluded that the decellularized Cb scaffold has great potential for promoting BM-MSCs proliferation and osteogenic differentiation., (© 2020 Wiley Periodicals LLC.)
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- 2021
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5. Comparative study between bone marrow mesenchymal stem cell and their conditioned medium in the treatment of rat model of Parkinsonism.
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Abdelwahab S, Elsebay SAG, Fouli Gaber M, and Abdel-Hafez SMN
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- Animals, Bone Marrow Cells drug effects, Cells, Cultured, Disease Models, Animal, Dopaminergic Neurons drug effects, Dopaminergic Neurons metabolism, Glial Fibrillary Acidic Protein metabolism, Male, Mesencephalon metabolism, Mesenchymal Stem Cells drug effects, Nestin metabolism, Neuropil drug effects, Neuropil metabolism, Parkinsonian Disorders drug therapy, Rats, Rotenone pharmacology, Stem Cells drug effects, Stem Cells metabolism, Substantia Nigra drug effects, Substantia Nigra metabolism, Synucleins metabolism, Bone Marrow Cells metabolism, Culture Media, Conditioned metabolism, Mesenchymal Stem Cells metabolism, Parkinsonian Disorders metabolism
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Parkinsonism is one of the most common aging neurodegenerative disorders. This study aims to compare the therapeutic effect of stem cell versus its conditioned medium in the Parkinsonism model. Parkinsonism was induced by daily subcutaneous injection of 0.5 mg/kg of rotenone dissolved in dimethyl sulfoxide for 28 days. Fifty rats were divided randomly into five groups: control, dimethyl sulfoxide, Parkinsonism, stem cell-treated, and conditioned medium-treated groups. Midbrain specimens were obtained for histological, immunohistochemical, and biochemical studies. Lewy bodies were observed in the Parkinsonism group in the dopaminergic neuron and neuropil as well. Almost all of the pathological changes were clearly ameliorated in both stem cell- and conditioned medium-treated groups as confirmed by biochemical, histological, and immunohistochemical (anti-nestin, anti-glial fibrillary acidic protein, and anti-α synuclein) studies. However, the conditioned medium showed more superior therapeutic effect establishing nearly the normal histological architecture of substantia nigra. These results may pave the future for using stem cell-conditioned medium as a more convenient and effective adjuvant therapy in Parkinsonism and other neurodegenerative disorders., (© 2020 Wiley Periodicals LLC.)
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- 2021
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6. Mesenchymal stromal cells; a new horizon in regenerative medicine.
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Tavakoli S, Ghaderi Jafarbeigloo HR, Shariati A, Jahangiryan A, Jadidi F, Jadidi Kouhbanani MA, Hassanzadeh A, Zamani M, Javidi K, and Naimi A
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- Animals, Cell Differentiation physiology, Cell Proliferation physiology, Humans, Bone Marrow Cells cytology, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells cytology, Regenerative Medicine methods
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In recent decades, mesenchymal stromal cells (MSCs) biomedical utilizing has attracted worldwide growing attention. After the first report of the human MSCs obtaining from the bone marrow (BM) tissue, these cells were isolated from wide types of the other tissues, ranging from adipose tissue to dental pulp. Their specific characteristics, comprising self-renewality, multipotency, and availability accompanied by their immunomodulatory properties and little ethical concern denote their importance in the context of regenerative medicine. Considering preclinical studies, MSCs can modify immune reactions during tissue repair and restoration, providing suitable milieu for tissue recovery; on the other hand, they can be differentiated into comprehensive types of the body cells, such as osteoblast, chondrocyte, hepatocyte, cardiomyocyte, fibroblast, and neural cells. Though a large number of studies have investigated MSCs capacities in regenerative medicine in varied animal models, the oncogenic capability of unregulated MSCs differentiation must be more assessed to enable their application in the clinic. In the current review, we provide a brief overview of MSCs sources, isolation, and expansion as well as immunomodulatory activities. More important, we try to collect and discuss recent preclinical and clinical research and evaluate current challenges in the context of the MSC-based cell therapy for regenerative medicine., (© 2020 Wiley Periodicals LLC.)
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- 2020
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7. Application of double network of gellan gum and pullulan for bone marrow stem cells differentiation towards chondrogenesis by controlling viscous substrates.
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Park A, Choi JH, Lee S, Been S, Song JE, and Khang G
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- Animals, Bone Marrow Cells drug effects, Bone Marrow Cells ultrastructure, Cell Death drug effects, Cell Shape drug effects, Cell Survival drug effects, Cells, Immobilized cytology, Cells, Immobilized drug effects, Cells, Immobilized ultrastructure, DNA metabolism, Female, Glycosaminoglycans metabolism, Hydrogels pharmacology, Rabbits, Spectroscopy, Fourier Transform Infrared, Stem Cells drug effects, Stem Cells ultrastructure, Viscosity, Bone Marrow Cells cytology, Cell Differentiation drug effects, Chondrogenesis drug effects, Glucans pharmacology, Polysaccharides, Bacterial pharmacology, Stem Cells cytology
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Hydrogels have a large amount of water that provides a cartilage-like environment and is used in tissue engineering with biocompatibility and adequate degradation rates. In order to differentiate stem cells, it is necessary to adjust the characteristics of the matrix such as stiffness, stress-relaxing time, and microenvironment. Double network (DN) hydrogels provide differences in cellular biological behavior and have interpenetrating networks that combine the advantages of the components. In this study, by varying the viscous substrate of pullulan (PL), the DN hydrogels of gellan gum (GG) and PL were prepared to determine the cartilage differentiation of bone marrow stem cell (BMSC). The characteristics of GG/PL hydrogel were investigated by examining the swelling ratio, weight loss, sol fraction, compressive modulus, and gelation temperature. The viability, proliferation, and toxicity of BMSCs encapsulated in hydrogels were evaluated. Cartilage phenotype and cartilage differentiation were confirmed by morphology, GAG content, and cartilage-specific gene expression. Overall results demonstrate that GG/PL hydrogels can form cartilage differentiation of BMSCs and can be applied for tissue engineering purposes., (© 2020 John Wiley & Sons, Ltd.)
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- 2020
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8. Accelerating bone defects healing in calvarial defect model using 3D cultured bone marrow-derived mesenchymal stem cells on demineralized bone particle scaffold.
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Kim JW, Park JH, Muthukumar T, Shin EY, Shin ME, Song JE, and Khang G
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- Animals, Bone Marrow Cells pathology, Female, Mesenchymal Stem Cells pathology, Rats, Rats, Sprague-Dawley, Bone Marrow Cells metabolism, Cell Culture Techniques, Cells, Immobilized metabolism, Cells, Immobilized pathology, Cells, Immobilized transplantation, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells metabolism, Skull injuries, Skull metabolism, Skull pathology, Tissue Scaffolds chemistry
- Abstract
Bone defects are usually difficult to be regenerated due to pathological states or the size of the injury. Researchers are focusing on tissue engineering approaches in order to drive the regenerative events, using stem cells to regenerate bone. The purpose of this study is to evaluate the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) on biologically derived Gallus gallus domesticus-derived demineralized bone particle (GDD) sponge. The sponges were prepared by freeze-drying method using 1, 2, and 3 wt% GDD and cross-linked with glutaraldehyde. The GDD sponge was characterized using scanning electron microscopy, compressive strength, porosity, and Fourier transform infrared. The potential bioactivity of the sponge was evaluated by osteogenic differentiation of BMSCs using 3(4, dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and quantifying alkaline phosphatase (ALP) activity. in vivo experiments were evaluated through a micro-computerized tomography (μ-CT) and histological assays. The analysis confirmed that an increase in the concentration of the GDD in the sponge leads to a higher bone formation and deposition in rat calvarial defects. Histological assay results were in line with μ-CT. The results reported in this study demonstrated the potential application of GDD sponges as osteoinductor in bone tissue engineering in pathological or nonunion bone defects., (© 2020 John Wiley & Sons, Ltd.)
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- 2020
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9. Different isoforms of growth hormone (20 kD-GH and 22 kD-GH) shows different biological activities in mesenchymal stem cell (MSC)
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Wei V. Zheng, Yaqin Li, Yanwei Xu, Donghui Lu, Tao Zhou, Dezhi Li, Xianyi Cheng, Yu Xiong, Shaobin Wang, and Zaizhong Chen
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Osteogenesis ,Growth Hormone ,Protein Isoforms ,Bone Marrow Cells ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Molecular Biology ,Research Paper ,Developmental Biology - Abstract
There are two main types of growth hormone (GH) in the circulatory system. One is 22 kD-GH, which is the predominant isoform in the circulating system, 90% GH is present as a 22 kD protein, and 10% of GH is present as a 20 kD protein. Amino acid sequences are identical between 20 kD-GH and 22 kD-GH protein, except that 20 kD-GH lacks 15 amino acid residues 32 to 46. Studies have shown that GH has many important biological effects on mesenchymal stem cells (MSCs). However, so far, the cellular characteristics of the two types of GH have not been studied in BM-MSCs. Furthermore, the biological activity of 20 kD-GH has not been explored in BM-MSCs. For this, in the current work, BM-MSCs were used as in vitro cell model. We have carried out the current research using a series of experimental techniques (such as Western-blot and indirect immunofluorescence). Firstly, we explored the cell behavior of two types of GH in the Bm-MSC model and found that they showed different biological characteristics; Secondly, we investigated the biological characteristics of 20 kD-GH and 22 kD-GH, and results showed that 22 kD-GH and 20 kD-GH exhibited different signaling profiles; Thirdly, we found that the 20 kD-GH and 22 kD-GH Gexhibited different regulatory effects on the osteogenic differentiation of BM-MSCs. The current research lays a solid foundation for further studies on the regulatory effects of GH on MSCs.
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- 2022
10. Regulatory effects of miR-28 on osteogenic differentiation of human bone marrow mesenchymal stem cells
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Min Wang, Tianming Dai, Qingqi Meng, Wen Wang, and Siming Li
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Adult ,Male ,osteogenic differentiation ,Bone Marrow Cells ,Cell Differentiation ,Mesenchymal Stem Cells ,Bioengineering ,General Medicine ,human bone marrow mesenchymal stem cell ,Middle Aged ,Applied Microbiology and Biotechnology ,MicroRNAs ,Osteogenesis ,Humans ,Female ,TP248.13-248.65 ,Mir-28 ,Research Article ,Research Paper ,Biotechnology - Abstract
We aimed to assess the regulatory effects of miR-28 on the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMMSCs). HBMMSCs isolated, cultured and induced (at P3) to undergo osteogenic induction. The expressions of miRNAs were detected by gene microarray, and differentially expressed miRNAs in hBMMSCs compared with induced cells were obtained by significance analysis of microarrays. The microarray findings were confirmed by RT-PCR. TargetScan showed that signal transducer and activator of transcription 1 (STAT1) was the downstream target gene of miR-28. The relationship between miR-28 and STAT1 was validated using dual-luciferase reporter gene assay. HBMMSCs were transfected with miR-28 mimics and STAT1 siRNA, respectively. Samples were collected on day 10 after osteogenic differentiation, and the alkaline phosphatase (AKP) activity, Runt-related transcription factor 2 (RUNX2, a key regulator of osteogenic differentiation) and STAT1 expressions were determined using kits, PCR and Western blotting, respectively. Cell proliferation and migration were detected through CCK-8 and Transwell assays, respectively. During the osteogenic differentiation of hBMMSCs, the expression level of miR-28 increased. MiR-28 specifically bound the 3’-untranslated region (3’UTR) of STAT1 mRNA. It inhibited STAT1 expression in a targeted manner during osteogenic differentiation. Interference with STAT1 partially mimicked the regulatory effects of miR-28 overexpression on the osteogenic differentiation of hBMMSCs. Interference with STAT1 or overexpression of miR-28 did not affect proliferation or migration. MiR-28 has gradually increased expression during the osteogenic differentiation of hBMMSCs, which can directly bind STAT1 3’UTR and inhibit its expression, thereby up-regulating AKP and RUNX2, and promoting osteogenic differentiation.
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- 2022
11. Methyl-CpG-binding protein 2 promotes osteogenic differentiation of bone marrow mesenchymal stem cells through regulating forkhead box F1/Wnt/β-Catenin axis
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Ji, Weiqin and Sun, Xiaotong
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congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,osteogenic differentiation ,Bone Marrow Cells ,Bioengineering ,bmscs ,Applied Microbiology and Biotechnology ,Mice ,stomatognathic system ,Osteogenesis ,Animals ,Wnt Signaling Pathway ,beta Catenin ,Forkhead Transcription Factors ,Mesenchymal Stem Cells ,General Medicine ,osteoporosis ,nervous system diseases ,foxf1/wnt/β-catenin ,estrogen deficiency ,Female ,mecp2 ,TP248.13-248.65 ,Research Article ,Research Paper ,Biotechnology - Abstract
Postmenopausal osteoporosis is characterized by inadequate bone formation of osteoblasts and excessive bone resorption of osteoclasts. Bone marrow mesenchymal stem cells (BMSCs), with the potential of osteogenic differentiation, have been widely used in the bone tissues engineering for the treatment of bone diseases, including postmenopausal osteoporosis. Methyl-CpG-binding protein 2 (MECP2) has been reported to be implicated in bone formation during the development of Rett syndrome. However, the influence of MeCP2 on osteogenic differentiation of BMSCs during osteoporosis remains unclear. Firstly, mice model with estrogen deficiency-induced osteoporosis was established through ovariectomy (OVX). MeCP2 was found to be down-regulated in bone tissues and BMSCs of OVX-induced osteoporosis mice. Secondly, over-expression of MeCP2 enhanced the calcium deposition of BMSCs isolated from the OVX-induced osteoporosis mice. Moreover, expression of osteogenic biomarkers including alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), collagen type I alpha 1 (COL1A1), and osteocalcin (OCN) was increased in BMSCs by overexpression of MeCP2. Thirdly, over-expression of MeCP2 reduced protein expression of forkhead box F1 (FOXF1) and adenomatous polyposis coli (APC), while enhanced Wnt5a and β-catenin expression in BMSCs. Over-expression of FOXF1 attenuated MeCP2 over-expression-induced decrease of FOXF1 and APC, as well as increase of Wnt5a and β-catenin. Finally, the increased calcium deposition, protein expression of ALP, RUNX2COL1A1 and OCN induced by concomitant overexpression of MeCP2 were also restored by FOXF1 over-expression. In conclusion, MeCP2 promoted osteogenic differentiation of BMSCs through regulating FOXF1/Wnt/β-Catenin axis to attenuate osteoporosis. MeCP2 over-expression reduced FOXF1 to promote the activation of Wnt5a/β-Catenin and promote osteogenic differentiation of BMSCs during the prevention of postmenopausal osteoporosis., Graphical Abstract
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- 2022
12. August Issue of Stem Cell Reviews and Reports Including a Spotlight Paper from Dr. Hal Broxmeyer on a Role of Brain in Regulating Hematopoiesis.
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Ratajczak, Mariusz Z.
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STEM cells , *HEMATOPOIESIS , *CYTOLOGY , *BONE marrow cells , *HEMATOPOIETIC stem cells , *SUPRACHIASMATIC nucleus - Abstract
However, as nicely discussed and summarized in this August issue, spotlight paper evidence demonstrates an active and beneficial dialogue between the central nervous system and hemato/lymphopoiesis. August Issue of Stem Cell Reviews and Reports Including a Spotlight Paper from Dr. Hal Broxmeyer on a Role of Brain in Regulating Hematopoiesis In this August issue of Stem Cell Reviews and Reports, we publish several exciting reviews and original papers on different types of stem cells. [Extracted from the article]
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- 2021
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13. Improved YOLOv7 Algorithm for Detecting Bone Marrow Cells.
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Cheng, Zhizhao and Li, Yuanyuan
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BONE marrow cells ,LIFTING & carrying (Human mechanics) ,BONE marrow ,ALGORITHMS - Abstract
The detection and classification of bone marrow (BM) cells is a critical cornerstone for hematology diagnosis. However, the low accuracy caused by few BM-cell data samples, subtle difference between classes, and small target size, pathologists still need to perform thousands of manual identifications daily. To address the above issues, we propose an improved BM-cell-detection algorithm in this paper, called YOLOv7-CTA. Firstly, to enhance the model's sensitivity to fine-grained features, we design a new module called CoTLAN in the backbone network to enable the model to perform long-term modeling between target feature information. Then, in order to cooperate with the CoTLAN module to pay more attention to the features in the area to be detected, we integrate the coordinate attention (CoordAtt) module between the CoTLAN modules to improve the model's attention to small target features. Finally, we cluster the target boxes of the BM cell dataset based on K-means++ to generate more suitable anchor boxes, which accelerates the convergence of the improved model. In addition, in order to solve the imbalance between positive and negative samples in BM-cell pictures, we use the Focal loss function to replace the multi-class cross entropy. Experimental results demonstrate that the best mean average precision (mAP) of the proposed model reaches 88.6%, which is an improvement of 12.9%, 8.3%, and 6.7% compared with that of the Faster R-CNN model, YOLOv5l model, and YOLOv7 model, respectively. This verifies the effectiveness and superiority of the YOLOv7-CTA model in BM-cell-detection tasks. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Restoration of aged hematopoietic cells by their young counterparts through instructive microvesicles release
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Khadidiatou Guiro, Lauren S. Sherman, Marina Gergues, Oleta A. Sandiford, Michael J. Schonning, Pranela Rameshwar, Robert J. Donnelly, Garima Sinha, Sri Harika Pamarthi, Seda Ayer, Steven J. Greco, Jean-Pierre Etchegaray, Markos H. El-Far, and Yannick Kenfack
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Adult ,Male ,Aging ,Myeloid ,bone marrow ,Inflammation ,Bone Marrow Cells ,Biology ,Young Adult ,Immune system ,Cell-Derived Microparticles ,microRNA ,medicine ,Humans ,Cellular Senescence ,miRNA ,Aged ,Secretome ,Cell Biology ,Middle Aged ,Fetal Blood ,In vitro ,Microvesicles ,hematopoiesis ,Haematopoiesis ,MicroRNAs ,medicine.anatomical_structure ,age ,Cancer research ,Female ,Bone marrow ,medicine.symptom ,microvesicles ,Research Paper - Abstract
This study addresses the potential to reverse age-associated morbidity by establishing methods to restore the aged hematopoietic system. Parabiotic animal models indicated that young secretome could restore aged tissues, leading us to establish a heterochronic transwell system with aged mobilized peripheral blood (MPB), co-cultured with young MPB or umbilical cord blood (UCB) cells. Functional studies and omics approaches indicate that the miRNA cargo of microvesicles (MVs) restores the aged hematopoietic system. The in vitro findings were validated in immune deficient (NSG) mice carrying an aged hematopoietic system, improving aged hallmarks such as increased lymphoid:myeloid ratio, decreased inflammation and cellular senescence. Elevated MYC and E2F pathways, and decreased p53 were key to hematopoietic restoration. These processes require four restorative miRs that target the genes for transcription/differentiation, namely PAX and phosphatase PPMIF. These miRs when introduced in aged cells were sufficient to restore the aged hematopoietic system in NSG mice. The aged MPBs were the drivers of their own restoration, as evidenced by the changes from distinct baseline miR profiles in MPBs and UCB to comparable expressions after exposure to aged MPBs. Restorative natural killer cells eliminated dormant breast cancer cells in vivo, indicating the broad relevance of this cellular paradigm - preventing and reversing age-associated disorders such as clearance of early malignancies and enhanced responses to vaccine and infection.
- Published
- 2021
15. Single-cell RNA sequencing deconvolutes the in vivo heterogeneity of human bone marrow-derived mesenchymal stem cells
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Hong-Wen Deng, Yun Gong, Zun Wang, Li-Jun Tan, Yang Junxiao, Yiping Chen, Xiang Qiu, Cui Zhou, Liang Cheng, Jonathan Greenbaum, Siyuan Tang, Hong-Mei Xiao, Yusheng Li, Martin R. Schiller, Xiaohua Li, Yu Chen, Huixi Zhang, Yihe Hu, Hui Shen, Yang Xucheng, Ying Liu, and Jie Xie
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Male ,Stromal cell ,bone marrow ,Bone Marrow Cells ,Nerve Tissue Proteins ,Receptors, Nerve Growth Factor ,Biology ,Muscle Development ,Applied Microbiology and Biotechnology ,Chondrocyte ,osteogenesis ,adipogenesis ,Mice ,Chondrocytes ,Bone Density ,chondrogenesis ,medicine ,Animals ,Cluster Analysis ,Humans ,Molecular Biology ,single-cell RNA sequencing (scRNA-seq) ,Ecology, Evolution, Behavior and Systematics ,Aged ,Aged, 80 and over ,Cluster of differentiation ,mesenchymal stem cell (MSC) ,Sequence Analysis, RNA ,Mesenchymal stem cell ,Osteoblast ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,CD56 Antigen ,Cell biology ,Mice, Inbred C57BL ,Haematopoiesis ,medicine.anatomical_structure ,Gene Expression Regulation ,Osteocyte ,Female ,Bone marrow ,Single-Cell Analysis ,Developmental Biology ,Research Paper - Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells that have a critical role in the maintenance of skeletal tissues such as bone, cartilage, and the fat in bone marrow. In addition to providing microenvironmental support for hematopoietic processes, BM-MSCs can differentiate into various mesodermal lineages including osteoblast/osteocyte, chondrocyte, and adipocyte that are crucial for bone metabolism. While BM-MSCs have high cell-to-cell heterogeneity in gene expression, the cell subtypes that contribute to this heterogeneity in vivo in humans have not been characterized. To investigate the transcriptional diversity of BM-MSCs, we applied single-cell RNA sequencing (scRNA-seq) on freshly isolated CD271+ BM-derived mononuclear cells (BM-MNCs) from two human subjects. We successfully identified LEPRhiCD45low BM-MSCs within the CD271+ BM-MNC population, and further codified the BM-MSCs into distinct subpopulations corresponding to the osteogenic, chondrogenic, and adipogenic differentiation trajectories, as well as terminal-stage quiescent cells. Biological functional annotations of the transcriptomes suggest that osteoblast precursors induce angiogenesis coupled with osteogenesis, and chondrocyte precursors have the potential to differentiate into myocytes. We also discovered transcripts for several clusters of differentiation (CD) markers that were either highly expressed (e.g., CD167b, CD91, CD130 and CD118) or absent (e.g., CD74, CD217, CD148 and CD68) in BM-MSCs, representing potential novel markers for human BM-MSC purification. This study is the first systematic in vivo dissection of human BM-MSCs cell subtypes at the single-cell resolution, revealing an insight into the extent of their cellular heterogeneity and roles in maintaining bone homeostasis.
- Published
- 2021
16. PiRNA-63049 inhibits bone formation through Wnt/β-catenin signaling pathway
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Zhenmin Wang, Zhizhong Li, Guozhi Xiao, Canling Long, Songlin Peng, Zhiteng Bao, He Xiaoqin, Chen Gaoyang, Wanze Tang, Xin Chen, Dazhi Yang, Tan Baoyu, William W. Lu, and Shang Wang
- Subjects
Stromal cell ,Ovariectomy ,Bone Marrow Cells ,Applied Microbiology and Biotechnology ,Bone resorption ,Bone remodeling ,Pathogenesis ,Bone Density ,Osteogenesis ,medicine ,Animals ,Humans ,RNA, Messenger ,RNA, Small Interfering ,Piwi-interacting RNAs ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,beta Catenin ,Aged ,Glycoproteins ,Bone Development ,Chemistry ,Stem Cells ,Bone marrow stromal cells ,Wnt signaling pathway ,Cell Biology ,Middle Aged ,Wnt signaling ,Rats ,Wnt Proteins ,medicine.anatomical_structure ,Gene Expression Regulation ,Bone formation ,Ovariectomized rat ,Cancer research ,Osteoporosis ,Female ,Bone marrow ,Signal transduction ,Developmental Biology ,Research Paper - Abstract
Bone remodeling is a dynamic process between bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. Disrupted bone remodeling is a key factor in postmenopausal osteoporosis, a metabolic disorder characterized by deteriorated bone microarchitecture and increased risk of fracture. Recent studies have shown that piwi-binding RNA (piRNA) is involved in the pathogenesis of certain diseases at the post-transcriptional level. Here, we analyzed piRNA-63049 (piR-63049), which may play an essential role in bone remodeling. The expression of piR-63049 significantly increased in both bone tissues and plasma of osteoporotic rats and postmenopausal osteoporotic patients. Overexpressing piR-63049 could inhibit the osteoblastogenesis of bone marrow stromal cells (BMSCs) while knocking down piR-63049 could promote the osteoblastogenesis of BMSCs through the Wnt2b/β-catenin signaling pathway. Moreover, knocking-down piR-63049 (piR-63049-antagonist) in vivo could attenuate the bone loss in ovariectomized rats by promoting bone formation. Taken together, the current study shows that piR-63049 inhibits bone formation through the Wnt2b/β-catenin signaling pathway. This novel piRNA may be a potential target to increase bone formation in bone loss disorders such as postmenopausal osteoporosis.
- Published
- 2021
17. Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system.
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Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, and Wang J
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- Animals, Bone Marrow Cells metabolism, Brain Ischemia metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Dinoprostone metabolism, Forkhead Transcription Factors metabolism, Immune Tolerance immunology, Male, Mice, Receptors, Prostaglandin E, EP4 Subtype metabolism, Sympathetic Nervous System metabolism, T-Lymphocytes, Regulatory metabolism, Bone Marrow Cells immunology, Brain Ischemia immunology, Signal Transduction immunology, Sympathetic Nervous System immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Recent evidence has shown that an increase in CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells may contribute to stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that stroke activates the sympathetic nervous system, which was abolished by 6-OHDA. The consequent activation of β2-adrenergic receptor (AR) signaling increased prostaglandin E2 (PGE2) level in bone marrow. β2-AR antagonist prevented the upregulation of PGE2. PGE2, which acts on prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-κB ligand (RANKL) in CD4(+) T cells and mediated the increase in Treg cells in bone marrow. Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells. PGE2 also elevated the expression of indoleamine 2,3 dioxygenase in CD11C(+) dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with indomethacin. Concurrently, stroke reduced production of stromal cell-derived factor-1 (SDF-1) via β3-AR signals in bone marrow but increased the expression of C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with β3-AR antagonist SR-59230A reduced the percent of Treg cells in peripheral blood after stroke. The disruption of the CXCR4-SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4(+) cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after stroke. We conclude that cerebral ischemia can increase bone marrow CD4(+)CD25(+)FoxP3(+) regulatory T cells via signals from the sympathetic nervous system., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2015
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18. Pure red cell aplasia among ABO mismatched hematopoietic stem cell transplant recipients: a 13-years retrospective study and literature review.
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Metafuni, Elisabetta, Busnego Barreto, Maria Teresa, Valentini, Caterina Giovanna, Giammarco, Sabrina, Limongiello, Maria Assunta, Sorà, Federica, Bianchi, Maria, Massini, Giuseppina, Piccirillo, Nicola, Putzulu, Rossana, Frioni, Filippo, Bacigalupo, Andrea, Teofili, Luciana, Chiusolo, Patrizia, and Sica, Simona
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PURE red cell aplasia ,STEM cell transplantation ,LITERATURE reviews ,HEMATOPOIETIC stem cells ,HEMATOPOIETIC stem cell transplantation ,BLOOD group incompatibility ,BONE marrow cells - Abstract
Background: Pure red cell aplasia (PRCA) is a possible complication after allogeneic hematopoietic stem cell transplantation (HSCT) with major ABO incompatibility. Patients experience delayed engraftment of the erythroid series, with prolonged transfusion-dependent anemia and iron overload. Methods: We performed a revision of the most recent literature about post-HSCT PRCA treatment procedures. Moreover, we conducted a retrospective study, over the last 13-years, which included all consecutive major ABO mismatched HSCT performed in our unit, with the aim to assess PRCA incidence, risk factors, and response to different treatments. Overall, 194 patients received a major ABO mismatched transplant from 2010 to 2022. For each patient, data about demographic and transplant characteristics, engraftment, blood transfusion, and possible treatment received were collected. Results: The literature review returned 23 eligible papers on PRCA treatment, with high success rate using plasma-exchange (PEX) and immunoadsorption procedures, daratumumab, and eltrombopag. Our study identified a total of 24 cases of PRCA. Among risk factors for PRCA development, we have found older recipient age (p=0.01), high pre-HSCT IgG and IgM IHA titer (p<0.0001), major rather than bidirectional ABO incompatibility (p=0.02), low T CD8 lymphocyte count in the graft (p=0.006), relative donor (p=0.02) and bone marrow as stem cell source (p=0.002). However, multivariate analysis confirmed only pre-HSCT IgG IHA titer as the unique risk factor for PRCA occurrence. The optimal cut-off value of pre-HSCT IgG IHA for PRCA development, resulted to be 1/64, with a 100% sensitivity and 68.8% specificity (p<0.0001). All patients with PRCA had received rhEPO and transfusion support and 20 patients received additional treatments like PEX, rituximab, and more recently daratumumab. Comprehensively, PEX and rituximab obtained a response in half of the cases, at a variable time, while the few cases of patients we treated with daratumumab suggest promising results. The overall response rate in our cohort was 75%, with significantly better survival (94.4% vs. 16.7%) and lower transplant-related mortality (6.3% vs. 80%) for PRCA responders. Conclusions: Standardized guidelines on when and how to treat PRCA are necessary because the current treatment is controversial among centers. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Transfection of STAT3 overexpression plasmid mediated through recombinant lentivirus promotes differentiation of bone marrow mesenchymal stem cells into neural cells in fetal rats with spina bifida aperta
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Mingyu Jiang, Mingyong Ren, Jicheng Dai, Chunming Jiang, Rong Fu, Xu Liu, Yanbo Pan, Yunpeng Hao, and Jiale Feng
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Male ,STAT3 Transcription Factor ,Aging ,Enolase ,Retinoic acid ,Bone Marrow Cells ,Tretinoin ,Biology ,Mesenchymal Stem Cell Transplantation ,Transfection ,Nestin ,Andrology ,chemistry.chemical_compound ,Fetus ,Western blot ,medicine ,Animals ,nerve cells ,Rats, Wistar ,signal transducer and activator of transcription-3 ,Tissue Engineering ,medicine.diagnostic_test ,Glial fibrillary acidic protein ,Lentivirus ,bone marrow mesenchymal stem cells ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Rats ,Transplantation ,Spina Bifida Cystica ,lentivirus transfection ,spina bifida aperta ,Spinal Cord ,chemistry ,biology.protein ,Female ,Research Paper ,Plasmids - Abstract
We investigated the influence of signal transducer and activator of transcription-3 (STAT3) on the spinal cord tissue grafts of rat fetuses with spina bifida aperta. In particular, we hoped to identify whether transfection of the STAT3 overexpression plasmid increases the survival of spinal cord transplantation in order to improve therapeutic efficacy. The fetal rat model of spina bifida aperta was established using retinoic acid and treated with a microsurgical injection of bone marrow mesenchymal stem cells (BMSCs). The animals were divided into either the blank control group, negative control group or the experimental group. The optical density (OD) value of BMSCs viability was determined using the Cell Counting Kit-8 (CCK-8). The expression of STAT3, phosphorylated STAT3 (pSTAT3), neural markers and apoptosis-related factors were evaluated using real-time PCR and Western blot. The OD value in the experimental group was highest at eight hours after transplantation using CCK-8. The expression of pSTAT3, glial fibrillary acidic protein, neuron-specific enolase, neurofilament and nestin in the experimental group was significantly higher compared to the blank control group and negative control group (P
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- 2021
20. The Chondrogenic Potential of First-Trimester and Term Placental Mesenchymal Stem/Stromal Cells
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Susan R. McGlashan, Anna E. S. Brooks, Claire N. Barker, Anandita Umapathy, Sonia Srinivasan, Ashika Chhana, Hilary M. Sheppard, Eloise Williams, Joanna L. James, and James I. Hearn
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Stromal cell ,Microarray ,Placenta ,Cartilage ,Cell ,Mesenchymal stem cell ,Biomedical Engineering ,Bone Marrow Cells ,Mesenchymal Stem Cells ,Physical Therapy, Sports Therapy and Rehabilitation ,Chondrocyte hypertrophy ,Biology ,Chondrogenesis ,Cell biology ,Glycosaminoglycan ,Pregnancy Trimester, First ,Chondrocytes ,medicine.anatomical_structure ,Pregnancy ,medicine ,Humans ,Immunology and Allergy ,Female ,Clinical Research papers - Abstract
Objectives Mesenchymal stem/stromal cells (MSCs) are a well-established cell source for cartilage engineering, but challenges remain as differentiation often results in chondrocyte hypertrophy. Chondrogenic potential also varies with MSC source and donor age. We assessed the chondrogenic potential of first-trimester and term placental MSCs and compared their response to commonly used bone marrow MSCs (BM-MSCs). Design MSCs were isolated from first-trimester and term placentae. BM-MSCs were commercially obtained. Chondrogenesis was induced by micromass culture in commercial chondrogenic media for 7, 14, or 21 days. Pellets were assessed for glycosaminoglycan (GAG) content, and types I, II, and X collagen. Gene expression was profiled using Qiagen RT2 human MSC arrays. Results At day 0, first-trimester and term MSCs expression levels of many chondrogenic genes to BM-MSC after 21 days of culture. Only first trimester MSCs showed significant changes in chondrogenic gene expression during induction compared to day 0 undifferentiated MSCs (greater BMP4, KAT2B, and reduced GDF6 expression). Additionally, first-trimester MSCs showed significantly greater expression of ABCB1 (at days 14 and 21) and BMP4 (at days 7, 14, 21) compared with term MSCs. Both first-trimester and term pellets showed increased GAG content over time and term MSCs had significantly GAG greater compared with BM-MSCs at days 7 and 14. Type II collagen was present in all pellets but unlike BM-MSCs, type I collagen was not observed in first-trimester or term MSC pellets. Conclusions These data highlight differences in BM-MSC and placental MSC chondrogenesis and demonstrate that placental MSCs may be an alternative cell source.
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- 2021
21. Neohesperidin promotes the osteogenic differentiation of human bone marrow stromal cells by inhibiting the histone modifications of lncRNA SNHG1
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Shuai Yuan, Chuanxin Zhang, Yi Chen, and Bo Wang
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Stromal cell ,Bone Marrow Cells ,Biology ,Flow cytometry ,stomatognathic system ,Osteogenesis ,medicine ,Humans ,Viability assay ,Molecular Biology ,Cells, Cultured ,medicine.diagnostic_test ,Hesperidin ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Cell biology ,Histone Code ,RUNX2 ,medicine.anatomical_structure ,H3K4me3 ,Alkaline phosphatase ,RNA, Long Noncoding ,Bone marrow ,Chromatin immunoprecipitation ,Research Paper ,Developmental Biology - Abstract
Neohesperidin (NH) was reported to regulate osteoclastic differentiation, while LncRNA SNHG1 could inhibit osteogenic differentiation of bone marrow stromal cells (BMSCs). In this study, we aimed to explore whether SNHG1-mediated osteogenic differentiation could be regulated by NH. Osteonecrosis and adjacent tissues, as well as normal bone marrow samples were gathered. BMSCs were isolated from normal bone marrow samples by Ficoll density gradient and identified by flow cytometry. Histopathological changes of tissues were detected by hematoxylin-eosin staining. After the treatment with NH or transfection, cell viability, osteogenic differentiation, and the activity of alkaline phosphatase (ALP) in BMSCs were detected by MTT, alizarin red staining, and microplate method, respectively. The histone modification and expressions of SNHG1 and osteogenic marker genes in tissues or BMSCs were detected by q-PCR and Chromatin Immunoprecipitation (ChIp). SNHG1 was highly expressed in osteonecrosis tissues, and typical signs of empty lacunae appeared in the necrotic tissues zone. NH increased viability and osteogenic differentiation of BMSCs, activity of ALP, and expressions of RUNX2, OCN and ALP. NH decreased both SNHG1 expression and H3K4me3 (activating histone modification) occupancies and increased H3K27me3 (inhibiting histone modification) occupancies of SNHG1. Furthermore, siSNHG1 enhanced osteogenic differentiation of BMSCs and expressions of RUNX2, OCN and ALP, while SNHG1 overexpression did the opposite and reversed the effects of NH on the osteogenic differentiation of BMSCs. In a word, NH promotes the osteogenic differentiation of human BMSCs by inhibiting the histone modifications of lncRNA SNHG1.
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- 2021
22. THBS4/integrin α2 axis mediates BM-MSCs to promote angiogenesis in gastric cancer associated with chronic Helicobacter pylori infection
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Weijun Wang, Huiying Shi, Yurui Zhang, Chen Jiang, Rong Lin, Hailing Yao, Wei Qian, and LingNan He
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Male ,Aging ,Angiogenesis ,Integrin alpha2 ,Mice, Nude ,Bone Marrow Cells ,Helicobacter Infections ,Mice ,Phosphatidylinositol 3-Kinases ,Bone Marrow ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,THBS4/Integrin α2 axis ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,Tube formation ,Mice, Inbred BALB C ,Helicobacter pylori ,Neovascularization, Pathologic ,biology ,business.industry ,Endothelial Cells ,Cancer ,bone marrow-derived mesenchymal stem cells (BM-MSCs) ,Mesenchymal Stem Cells ,tumor angiogenesis ,Cell Biology ,medicine.disease ,biology.organism_classification ,Xenograft Model Antitumor Assays ,gastric cancer (GC) ,PI3K/AKT pathway ,Chorioallantoic membrane ,medicine.anatomical_structure ,Cancer research ,Human umbilical vein endothelial cell ,Thrombospondins ,business ,Research Paper ,Signal Transduction ,Blood vessel - Abstract
Background BM-MSCs contribute to Helicobacter pylori (H. pylori)-induced gastric cancer, but their mechanism is still unclear. The aim of our study was to investigate the specific role and mechanism of BM-MSCs in H. pylori-induced gastric cancer. Main methods Mice received total bone marrow transplants and were then infected with H. pylori. BM-MSCs were extracted and transplanted into the gastric serosal layer of mice chronically infected with H. pylori. Hematoxylin and eosin staining, immunohistochemistry staining and immunofluorescence were performed to detect tumor growth and angiogenesis in mouse stomach tissues. Chicken chorioallantoic membrane assays, xenograft tumor models, and human umbilical vein endothelial cell tube formation assays were used for in vivo and in vitro angiogenesis studies. THBS4 was screened from RNA-seq analysis of gastric tissues of BM-MSCs transplanted into H. pylori-infected mice. Results BM-MSCs can migrate to the site of chronic mucosal injury and promote tumor angiogenesis associated with chronic H. pylori infection. Migration of BM-MSCs to the site of chronic mucosal injury induced the upregulation of THBS4, which was also evident in human gastric cancer and correlated with increased blood vessel formation and worse outcome. The THBS4/integrin α2 axis promoted angiogenesis by facilitating the PI3K/AKT pathway in endothelial cells. Conclusions Our results revealed a novel proangiogenic effect of BM-MSCs in the chronic H. pylori infection microenvironment, primarily mediated by the THBS4/integrin α2 axis, which activates the PI3K/AKT pathway in endothelial cells and eventually induces the formation of new tumor vessels.
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- 2021
23. miR-424-5p shuttled by bone marrow stem cells-derived exosomes attenuates osteogenesis via regulating WIF1-mediated Wnt/β-catenin axis
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Hanrong Yin, Yongcai Song, Haiqing Zhou, Huiling Ma, Yongkun Wei, Jie Yang, and Binhui Yang
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Aging ,Osteocalcin ,Bone Marrow Cells ,Core Binding Factor Alpha 1 Subunit ,exosomes ,WIF1 ,bone marrow stem cells ,Exosome ,osteogenesis ,Western blot ,stomatognathic system ,medicine ,Humans ,Wnt Signaling Pathway ,Adaptor Proteins, Signal Transducing ,Wnt/β-catenin ,Osteoblasts ,medicine.diagnostic_test ,Chemistry ,Stem Cells ,Wnt signaling pathway ,Bone Marrow Stem Cell ,Cell Differentiation ,Cell Biology ,Microvesicles ,Cell biology ,RUNX2 ,MicroRNAs ,Catenin ,Research Paper - Abstract
Emerging evidence proves that exosomes contain specific microRNAs(miRNAs) contribute to osteogenic differentiation of bone marrow stem cells (BMSCs). However, the role and mechanism of bone marrow stem cells (BMSCs)-derived exosomes overexpressing miR-424-5p in osteoblasts remains unclear. Firstly, the BMSCs-derived exosomes were isolated, and identified by Western blot with the exosome surface markers CD9, CD81 and CD63. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to detect the level of miR-424-5p in exosomes, and western blot was implemented to verify the WIF1/Wnt/β-catenin expression. The binding association between miR-424-5p and WIF1 was determined by the dual-luciferase reporter gene assay. Functional enhancement experiments were adopted to determine the role of exosome-carried miR-424-5p and WIF1/Wnt/β-catenin in osteogenic differentiation. ALP staining was adopted, and levels of RUNX2, OCN, and OPN were monitored using qRT-PCR to determine osteogenic differentiation. As a result, In vivo experiments showed that RUNX2, OCN and OPN levels decreased and the ALP activity was dampened after miR-424-5p overexpression in exosomes. Besides, exosomes overexpressing miR-424-5p attenuated osteogenic development via WIF1/Wnt/β-catenin. Our findings may bring evidence for miR-424-5p as a new biomarker for the treatment of osteoporosis.
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- 2021
24. Age-related defects in autophagy alter the secretion of paracrine factors from bone marrow mononuclear cells
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Ren-Ke Li, Richard D. Weisel, Jun Wu, Fievel Lim, Stephanie W. Tobin, Shu-Hong Li, Faisal J. Alibhai, and Azadeh Yeganeh
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Senescence ,autophagy ,Aging ,bone marrow ,Bone Marrow Cells ,Autophagy-Related Protein 7 ,Transforming Growth Factor beta1 ,Cell therapy ,Extracellular Vesicles ,Paracrine signalling ,Paracrine Communication ,medicine ,Animals ,Antigens, Ly ,Secretion ,Fibroblast ,business.industry ,Myocardium ,Autophagy ,Membrane Proteins ,Cell Biology ,Extracellular vesicle ,Fibroblasts ,Mice, Inbred C57BL ,secretome ,medicine.anatomical_structure ,Culture Media, Conditioned ,Leukocytes, Mononuclear ,Cancer research ,Bone marrow ,business ,Research Paper - Abstract
Bone marrow mononuclear cell therapy improves cardiac repair after myocardial infarction (MI), in-part through signaling to resident cardiac cells, such as fibroblasts, which regulate scar formation. The efficacy of cell therapy declines with age, as aging of both donor and recipient cells decreases repair responses. Autophagy regulates the microenvironment by both extracellular vesicle (EV)-dependent and independent secretion pathways. We hypothesized that age-related autophagy changes in bone marrow cells (BMCs) alter paracrine signaling, contributing to lower cell therapy efficacy. Here, we demonstrate that young Sca-1+ BMCs exhibited a higher LC3II/LC3I ratio compared to old Sca-1+ BMCs, which was accentuated when BMCs were cultured under hypoxia. To examine the effect on paracrine signaling, old cardiac fibroblasts were cultured with conditioned medium (CM) from young and old Sca-1+ BMCs. Young, but not old CM, enhanced fibroblast proliferation, migration, and differentiation, plus reduced senescence. These beneficial effects were lost when autophagy or EV secretion in BMCs was blocked pharmacologically, or by siRNA knockdown of Atg7. Therefore, both EV-dependent and -independent paracrine signaling from young BMCs is responsible for paracrine stimulation of old cardiac fibroblasts. In vivo, bone marrow chimerism of old mice with young BMCs increased the number of LC3b+ cells in the heart compared to old mice reconstituted with old BMCs. These data suggest that the deterioration of autophagy with aging negatively impacts the paracrine effects of BMCs, and provide mechanistic insight into the age-related decline in cell therapy efficacy that could be targeted to improve the function of old donor cells.
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- 2021
25. Mesenchymal stem cells-derived extracellular vesicles ameliorate Alzheimer’s disease in rat models via the microRNA-29c-3p/BACE1 axis and the Wnt/β-catenin pathway
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sha sha, Le Qu, Yunpeng Cao, and Xueli Shen
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Male ,Aging ,Bone Marrow Cells ,Hippocampus ,Models, Biological ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,Extracellular Vesicles ,Alzheimer Disease ,microRNA ,Gene silencing ,Animals ,Aspartic Acid Endopeptidases ,microRNA-29c-3p ,Wnt Signaling Pathway ,Neurons ,Gene knockdown ,Base Sequence ,Chemistry ,Mesenchymal stem cell ,Wnt signaling pathway ,bone marrow mesenchymal stem cells ,BACE1 ,Mesenchymal Stem Cells ,Cell Biology ,Alzheimer's disease ,Cell biology ,Disease Models, Animal ,MicroRNAs ,DKK1 ,Catenin ,Female ,Amyloid Precursor Protein Secretases ,Research Paper - Abstract
Currently, Alzheimer's disease (AD) cannot be treated effectively. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) (MSC-EVs) exhibit therapeutic effects on many diseases. This study investigated the mechanism of bone marrow MSC-EVs (BM-MSC-EVs) in a rat model of AD. The cognitive function, amyloid-β (Aβ) plaques, Aβ deposition areas and levels of Aβ1-42, Aβ decomposition-related factors (NEP and IDE), and inflammatory cytokines in BM-MSC-EVs-treated AD rats were measured. The effect of BM-MSC-EVs was studied in AD neuron model. microRNA (miR)-29c-3p and BACE1 expression, as well as levels of Wnt/β-catenin pathway-related factors in AD and EVs-treated AD models were detected. miR-29c-3p relationship with BACE1 was predicted and confirmed. miR-29c-3p and BACE1 were interfered to verify the mechanism of EVs in AD. The Wnt/β-catenin pathway inhibitor DKK1 was further added to EVs-treated AD neurons. BM-MSC-EVs showed therapeutic effects on AD rats and neurons. BM-MSC-EVs carried miR-29c-3p into AD neurons. miR-29c-3p targeted BACE1. Silencing miR-29c-3p in BM-MSCs reduced BM-MSC-EV therapeutic effect on AD, which was reversed after BACE1 knockdown. miR-29c-3p targeted BACE1 and activated the Wnt/β-catenin pathway, and the Wnt/β-catenin pathway inhibition impaired EV therapeutic effects on AD. We highlighted that BM-MSC-EVs delivered miR-29c-3p to neurons to inhibit BACE1 expression and activate the Wnt/β-catenin pathway, thereby playing a therapeutic role in AD. This study may provide a novel perspective for elucidating the mechanism of MSCs in the treatment of AD.
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- 2021
26. Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment
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Elizabeth C. Stahl, Siddhartha Dash, Bryan N. Brown, Branimir Popovich, Samuel T. LoPresti, and Martin J. Haschak
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Aging ,medicine.medical_treatment ,Macrophage polarization ,Nitric Oxide Synthase Type II ,Bone Marrow Cells ,macrophage ,Nitric Oxide ,Nitric oxide ,Extracellular matrix ,Tissue Culture Techniques ,chemistry.chemical_compound ,Mice ,medicine ,Macrophage ,Animals ,biology ,Arginase ,Chemistry ,cardiovascular ,Macrophages ,Myocardium ,Cardiac muscle ,Heart ,Cell Biology ,DNA ,Macrophage Activation ,microenvironment ,Cell biology ,Biomechanical Phenomena ,Nitric oxide synthase ,Mice, Inbred C57BL ,Cytokine ,medicine.anatomical_structure ,Phenotype ,Cellular Microenvironment ,biology.protein ,Cytokines ,Research Paper ,Signal Transduction - Abstract
Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naive bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.
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- 2021
27. Aging impairs human bone marrow function and cardiac repair following myocardial infarction in a humanized chimeric mouse
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Tina Binesh Marvasti, Faisal J. Alibhai, Shu-Hong Li, Maral Ouzounian, Robert J. Cusimano, Ren-Ke Li, Terrence M. Yau, Jun Wu, Anne Fu, Lukasz Wlodarek, and Richard D. Weisel
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Male ,medicine.medical_specialty ,Aging ,CD34 ,Myocardial Infarction ,Neovascularization, Physiologic ,Spleen ,Antigens, CD34 ,Bone Marrow Cells ,Mice, SCID ,030204 cardiovascular system & hematology ,Biology ,Cohort Studies ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Mice, Inbred NOD ,Internal medicine ,medicine ,Animals ,Humans ,Myocardial infarction ,Ventricular remodeling ,030304 developmental biology ,Aged ,Bone Marrow Transplantation ,0303 health sciences ,Original Paper ,Ventricular Remodeling ,Cell Biology ,bone marrow transplant ,Middle Aged ,medicine.disease ,Original Papers ,Coronary Vessels ,3. Good health ,Disease Models, Animal ,Lymphatic system ,Endocrinology ,medicine.anatomical_structure ,humanized mice ,Heart failure ,Radiation Chimera ,Female ,Bone marrow - Abstract
Ventricular remodeling following myocardial infarction (MI) is a major cause of heart failure, a condition prevalent in older individuals. Following MI, immune cells are mobilized to the myocardium from peripheral lymphoid organs and play an active role in orchestrating repair. While the effect of aging on mouse bone marrow (BM) has been studied, less is known about how aging affects human BM cells and their ability to regulate repair processes. In this study, we investigate the effect aging has on human BM cell responses post‐MI using a humanized chimeric mouse model. BM samples were collected from middle aged (mean age 56.4 ± 0.97) and old (mean age 72.7 ± 0.59) patients undergoing cardiac surgery, CD34+/− cells were isolated, and NOD‐scid‐IL2rγnull (NSG) mice were reconstituted. Three months following reconstitution, the animals were examined at baseline or subjected to coronary artery ligation (MI). Younger patient cells exhibited greater repopulation capacity in the BM, blood, and spleen as well as greater lymphoid cell production. Following MI, CD34+ cell age impacted donor and host cellular responses. Mice reconstituted with younger CD34+ cells exhibited greater human CD45+ recruitment to the heart compared to mice reconstituted with old cells. Increased cellular responses were primarily driven by T‐cell recruitment, and these changes corresponded with greater human IFNy levels and reduced mouse IL‐1β in the heart. Age‐dependent changes in BM function led to significantly lower survival, increased infarct expansion, impaired host cell responses, and reduced function by 4w post‐MI. In contrast, younger CD34+ cells helped to limit remodeling and preserve function post‐MI., To study the effect aging has on human cell responses post‐MI, we utilized a xenograft mouse (NSG) model using BM from middle aged (Y‐CD34+) and old patients (O‐CD34+). Our results demonstrate that O‐CD34+ reconstituted mice exhibit impaired donor and host cell responses while Y‐CD34+ reconstituted mice exhibit a greater donor lymphocyte and host myeloid cell responses post‐MI. Differences in cellular responses are associated with improved cardiac function in Y‐CD34+ reconstituted mice post‐MI.
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- 2021
28. Bone marrow stem cells secretome accelerates simulated birth trauma-induced stress urinary incontinence recovery in rats
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Jia-Hui Liu, Ming-Hui Jiang, Hongbing Liao, Hai-Hong Jiang, Xiao-Liang Zhu, Hai-Yan Li, Yasmeen Bano, and Wen-Li Liu
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Aging ,Angiogenesis ,Birth trauma ,Urinary Incontinence, Stress ,Rat model ,Bone Marrow Cells ,Urinary incontinence ,bone marrow stem cells ,Andrology ,medicine ,Animals ,Enzyme Inhibitors ,Cell adhesion ,STAT4 ,Cell Proliferation ,business.industry ,Parturition ,Bone Marrow Stem Cell ,Mesenchymal Stem Cells ,JAK2/STAT4 ,Cell Biology ,Fibroblasts ,Tyrphostins ,medicine.disease ,stress urinary incontinence ,Rats ,secretome ,Induced stress ,Culture Media, Conditioned ,Vagina ,Female ,Collagen ,medicine.symptom ,business ,Research Paper ,Signal Transduction - Abstract
Stress urinary incontinence (SUI) is defined as involuntary urine leakage during physical activities that increase the intra-abdominal pressure on the bladder. We studied bone marrow stem cell (BMSC) secretome-induced activation of anterior vaginal wall (AVW) fibroblasts and its ability to accelerate SUI recovery following vaginal distention (VD) in a rat model of birth trauma using BMSC-conditioned medium (BMSC-CM) and concentrated conditioned medium (CCM). BMSC-CM enhanced the proliferation, migration, and collagen synthesizing abilities of fibroblasts. Differentially expressed genes in BMSC-CM-induced fibroblasts were mainly enriched for cell adhesion, extracellular fibril organization and angiogenesis. Treatment with the JAK2 inhibitor AG490 reversed BMSC-CM-induced activation of the JAK2/STAT4 pathway. Periurethral injection with BMSC-CCM markedly enhanced the abdominal leak point pressure (LPP) in rats after VD. Histological analysis revealed increased numbers of fibroblasts, improved collagen fibers arrangement and elevated collagens content in the AVW of rats receiving BMSC-CCM. These findings suggest the BMSC secretome activates AVW fibroblasts and contributes to the functional and anatomic recovery of simulated birth trauma-induced SUI in rats.
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- 2021
29. Bone mesenchymal stem cell-derived extracellular vesicles promote the repair of intervertebral disc degeneration by transferring microRNA-199a
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Yongpeng Lin, Jinggong Liu, Yongjin Li, Bolai Chen, Shuai Zhao, Tao Wen, and Hong-Shen Wang
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Male ,0301 basic medicine ,Cell ,Bone Marrow Cells ,Intervertebral Disc Degeneration ,Biology ,Mesenchymal Stem Cell Transplantation ,Extracellular Vesicles ,Mice ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,microRNA ,medicine ,Animals ,Molecular Biology ,Cells, Cultured ,Aggrecan ,TIMP1 ,Mice, Inbred BALB C ,Lumbar Vertebrae ,Microarray analysis techniques ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Rats ,Cell biology ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Apoptosis ,030220 oncology & carcinogenesis ,Research Paper ,Developmental Biology ,Transforming growth factor - Abstract
Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) protect intervertebral disc degeneration (IDD) by regulating nucleus pulposus cell (NPC) apoptosis. But the mechanism of BMSCs-EVs-microRNA (miR)-199a in IDD remains unclear. In this study, after the acquisition and identification of BMSCs and BMSCs-EVs, IDD mouse model was established and treated with BMSCs-EVs. The pathological changes of NPCs, positive expression of MMP-2, MMP-6 and TIMP1, and the senescence and apoptosis of NPCs were evaluated. Microarray analysis was employed to analyze the differentially expressed miRs and genes after EV treatment. NPCs were treated with EVs/miR-199a/TGF-β agonist SRI-011381. The positive expression of col II and Aggrecan was assessed. The target gene and downstream pathway of miR-199a were analyzed. In vivo experiment, after BMSCs-EV treatment, MMP-2, MMP-6, TIMP1 and TUNEL-positive cells in IDD mice were decreased, and miR-199a was increased. In vitro experiments, the expression of col Ⅱ and Aggrecan, SA-β gal positive cells and apoptosis rate of NPCs were decreased after EV intervention. The protective effect of BMSCs-EVs on NPCs was impaired by reducing miR-199a carried by EVs. miR-199a could target GREM1 to inactivate the TGF-β pathway. miR-199a carried by BMSCs-EVs promotes IDD repair by targeting GREM1 and downregulating the TGF-β pathway. Our work confers a promising therapeutic strategy for IDD.
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- 2021
30. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss
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Hongbing Jiang, Jie Cheng, Yu Fu, Xin Shen, Hengguo Zhang, Dingshan Liu, Hanyu Xie, Rongyao Xu, Xin Chen, Yi Yang, and Ping Zhang
- Subjects
0301 basic medicine ,Extracellular Vesicles (EVs) ,Osteoporosis ,Osteoclasts ,Medicine (miscellaneous) ,Bone Mesenchymal Stem Cells (BMSCs) ,Mice ,0302 clinical medicine ,Osteogenesis ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cells, Cultured ,Osteoporosis, Postmenopausal ,Mice, Knockout ,Cell Differentiation ,Chromatin ,Cell biology ,medicine.anatomical_structure ,core transcription factors (TFs) ,Female ,RNA, Long Noncoding ,miR-143/145 ,Research Paper ,Adult ,Bone Marrow Cells ,Biology ,Bone and Bones ,Bone resorption ,Extracellular Vesicles ,03 medical and health sciences ,SOX2 ,microRNA ,medicine ,Animals ,Humans ,Bone Resorption ,Transcription factor ,Aged ,Osteoblasts ,Competing endogenous RNA ,Estrogens ,Mesenchymal Stem Cells ,medicine.disease ,Estrogen ,Mice, Inbred C57BL ,Bone Diseases, Metabolic ,MicroRNAs ,HEK293 Cells ,030104 developmental biology ,Bone marrow ,030217 neurology & neurosurgery - Abstract
Rationale: Postmenopausal-induced bone loss is mainly caused by declining core transcription factors (TFs) of bone mesenchymal stem cells (BMSCs), but little is known about how miRNAs regulate chromatin structure remodeling of TFs gene to maintain BMSCs function in bone homeostasis. Methods: We examined the serum, salivary and bone samples from Pre- and Post-menopause women by paired analysis and confirmed canonical ceRNA role of MIR143HG and miR-143/145 complexes in cytoplasm and noncanonical role for SOX2 transcription in nucleus (FISH, qRT-PCR, immunostaining, Luciferase assays and ChIP). Moreover, we took advantage of transgenic mice under OVX-induced osteoporosis, studying the in vitro and in vivo effect of miR-143/145 deletion on BMSCs function and bone homeostasis. Last, using miRNA antagonism, antagomiR-143/145 were delivered into bone marrow to treat estrogen-deficient bone loss. Results: Here, we identified miR-143/145 as potential diagnostic candidates for postmenopausal osteoporosis, and miR-143/145 overexpression impaired BMSCs self-renewing and differentiation function. Mechanistically, we confirmed that cytoplasmic miR-143/145 and LncRNA MIR143HG, that controlled by ERβ, cooperatively regulated pluripotency genes translation via canonical ceRNA pathway, and MIR143HG cooperates with miR‑143 to nuclear translocation for co-activation of SOX2 transcription via opening promoter chromatin. Meanwhile, miR‑143/145 were shuttled into osteoclasts in extracellular vesicles and triggered osteoclastic activity by targeting Cd226 and Srgap2. Furthermore, miR-143/145-/- mice or using chemically‑modified antagomiR-143/145 significantly alleviated estrogen-deficient osteoporosis. Conclusions: Our findings reveal a canonical and noncanonical role of miR-143/145 in controlling BMSCs pluripotency and unfold their dual effect on bone formation and bone resorption, suggesting miR-143/145 as promising therapeutic targets for treating estrogen-deficient bone loss.
- Published
- 2021
31. Vertebral-specific activation of the CX3CL1/ICAM-1 signaling network mediates non-small-cell lung cancer spinal metastasis by engaging tumor cell-vertebral bone marrow endothelial cell interactions
- Author
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Feng Zhang, Xiaogang Zhou, Yiwei Huang, Lei Zhou, Annan Hu, Libo Jiang, Qing Chen, Jian Dong, Ketao Wang, and Chi Sun
- Subjects
Male ,0301 basic medicine ,Chemokine ,Lung Neoplasms ,ICAM-1 ,Medicine (miscellaneous) ,Bone Marrow Cells ,CX3CL1 ,Metastasis ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Non-small cell lung cancer ,Carcinoma, Non-Small-Cell Lung ,Humans ,Medicine ,Lung cancer ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,PI3K/AKT/mTOR pathway ,Aged ,Spinal Neoplasms ,biology ,Chemokine CX3CL1 ,business.industry ,Transendothelial and Transepithelial Migration ,Endothelial Cells ,Middle Aged ,Intercellular Adhesion Molecule-1 ,medicine.disease ,Lymphocyte Function-Associated Antigen-1 ,Spine ,Extravasation ,respiratory tract diseases ,Endothelial stem cell ,extravasation ,030104 developmental biology ,spinal metastasis ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Paper - Abstract
Rationale: The spine is one of the most common metastatic sites of non-small cell lung cancer (NSCLC), and NSCLC spinal metastasis results in serious consequences. Metastatic extravasation of disseminated cancer cells including increased invasiveness, adhesion and transendothelial migration is crucial for tumor metastasis. This study aimed to investigate the mechanisms underlying NSCLC spinal metastasis based on the C-X3-C motif chemokine ligand 1- (CX3CL1) and intercellular adhesion molecule-1- (ICAM-1) mediated signaling network. Methods: Immunohistochemistry, western blotting, and reverse transcription-quantitative PCR were conducted to detect the distribution of CX3CL1/ICAM-1 in different organs. Transwell, adhesion, and transendothelial migration assays were performed to evaluate the regulatory effects of CX3CL1/ICAM-1 on NSCLC cell invasion, adhesion, and transendothelial migration in vitro. A spontaneous spinal metastasis mouse model was established via injection of NSCLC cells into the left cardiac ventricle of NOD/SCID mice. The effects of CX3CL1/ICAM-1 on NSCLC spinal metastasis in vivo were validated using bioluminescent, micro-computerized tomography, immunohistochemistry and histological analyses. Results: CX3CL1 expression was specifically higher in vertebral bone compared with limb bones and lung tissue, and was associated with NSCLC spinal metastasis. Mechanically, vertebral bone marrow endothelial cells (VBMECs) enhanced NSCLC cell invasion via CX3CL1 signaling-mediated activation of the PI3K/AKT pathway. Furthermore, we found that VBMECs effectively induced ICAM-1-dependent NSCLC cell adhesion in coordination with platelets through the CX3CL1/ICAM-1/LFA-1 pathway. Meanwhile, CX3CL1 enhanced NSCLC cell transendothelial migration by increasing permeability of VBMECs via ICAM-1-dependent activation of the Src/GEF-H1 pathway. Interestingly, NSCLC cells were indicated to promote CX3CL1 secretion of VBMECs through MAPK14/ADMA17-dependent CX3CL1 release and NF-κB-dependent CX3CL1 synthesis. Based on these findings, we revealed a novel feedback cycle between circulating NSCLC cells and VBMECs mediated by CX3CL1/ICAM-1 signaling. Further disengagement of the CX3CL1/ICAM-1-mediated feedback cycle in vivo significantly restricted metastasis and prolonged mouse survival. Conclusions: Our results indicated a unique feedback cycle between circulating NSCLC cells and VBMECs mediated by CX3CL1/ICAM-1 signaling, which is necessary for NSCLC spinal metastasis. This work provides a new perspective for underlying the mechanisms of NSCLC spinal metastasis and indicates potential novel targets for the prevention of NSCLC spinal metastasis.
- Published
- 2021
32. Hematopoietic stem cells produce intermediate lineage adipocyte progenitors that simultaneously express both myeloid and mesenchymal lineage markers in adipose tissue
- Author
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Susan M. Majka, Alistair S Acosta, Kathleen M. Gavin, Wendy M. Kohrt, Timothy M Sullivan, Dwight J. Klemm, Joanne K Maltzahn, and Jeremy T Rahkola
- Subjects
Histology ,Physiology ,Adipose tissue ,Bone Marrow Cells ,haematopoietic stem cell ,Biology ,mesenchymal ,Stem cell marker ,adipocyte ,Diseases of the endocrine glands. Clinical endocrinology ,Mice ,chemistry.chemical_compound ,Adipocyte ,Adipocytes ,medicine ,Animals ,QP1-981 ,QH573-671 ,Lineage markers ,Mesenchymal stem cell ,Cell Differentiation ,progenitor ,Cell Biology ,Hematopoietic Stem Cells ,RC648-665 ,Cell biology ,medicine.anatomical_structure ,Adipose Tissue ,chemistry ,Adipogenesis ,Bone marrow ,Stem cell ,myeloid ,Cytology ,Research Article ,Research Paper - Abstract
Some adipocytes are produced from bone marrow hematopoietic stem cells. In vitro studies previously indicated that these bone marrow-derived adipocytes (BMDAs) were generated from adipose tissue macrophage (ATM) that lose their hematopoietic markers and acquire mesenchymal markers prior to terminal adipogenic differentiation. Here we interrogated whether this hematopoietic-to-mesenchymal transition drives BMDA production In vitro. We generated transgenic mice in which the lysozyme gene promoter (LysM) indelibly labeled ATM with green fluorescent protein (GFP). We discovered that adipose stroma contained a population of LysM-positive myeloid cells that simultaneously expressed hematopoietic/myeloid markers (CD45 and CD11b), and mesenchymal markers (CD29, PDGFRa and Sca-1) typically found on conventional adipocyte progenitors. These cells were capable of adipogenic differentiation In vitro and In vitro, while other stromal populations deficient in PDGFRa and Sca-1 were non-adipogenic. BMDAs and conventional adipocytes expressed common fat cell markers but exhibited little or no expression of hematopoietic and mesenchymal progenitor cell markers. The data indicate that BMDAs are produced from ATM simultaneously expressing hematopoietic and mesenchymal markers rather than via a stepwise hematopoietic-to-mesenchymal transition. Because BMDA production is stimulated by high fat feeding, their production from hematopoietic progenitors may maintain adipocyte production when conventional adipocyte precursors are diminished.
- Published
- 2021
33. Decorin inhibits the insulin-like growth factor I signaling in bone marrow mesenchymal stem cells of aged humans
- Author
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Kuo-Yun Tseng, Zih-Ying Chen, Tze-Hong Wong, Chung-Hsing Chen, Shankung Lin, Feng-Huei Lin, Ting-Yu Chen, and Hung-Ming Wu
- Subjects
Adult ,Aging ,Decorin ,medicine.medical_treatment ,Bisulfite sequencing ,Bone Marrow Cells ,Decitabine ,Receptor, IGF Type 1 ,Insulin-like growth factor ,otorhinolaryngologic diseases ,medicine ,Humans ,RNA, Messenger ,Enzyme Inhibitors ,Insulin-Like Growth Factor I ,Phosphorylation ,Receptor ,Aged ,Gene knockdown ,Chemistry ,Gene Expression Regulation, Developmental ,Mesenchymal Stem Cells ,Cell Biology ,Methylation ,DNA Methylation ,Middle Aged ,osteoporosis ,Amino Acids, Dicarboxylic ,IGF-I ,Cell biology ,DNA Demethylation ,DNA demethylation ,bone marrow mesenchymal stem cell ,CpG site ,Gene Knockdown Techniques ,small leucine-rich proteoglycan ,Signal Transduction ,Research Paper - Abstract
Aging impairs the IGF-I signaling of bone marrow mesenchymal stem cells (bmMSCs), but the mechanism is unclear. Here, we found that the ability to auto-phosphorylate IGF-I receptor (IGF-IR) in response to IGF-I was decreased in the bmMSCs of aged donors. Conversely, data showed that decorin (DCN) expression was prominently increased in aged bmMSCs, and that under IGF-I treatment, DCN knockdown in serum-starved aged bmMSCs potentiated their mitogenic activity and IGF-IR auto-phosphorylation, whereas DCN overexpression in serum-starved adult bmMSCs decreased both activities. Co-immunoprecipitation assays suggested that IGF-I and DCN bound to IGF-IR in a competitive manner. Online MethPrimer predicted 4 CpG islands (CGIs) in the introns of DCN gene. RT-qPCR and bisulfite sequencing showed that dimethyloxalylglycine, an inhibitor of DNA demethylation, increased DCN mRNA expression and CGI-I methylation in adult bmMSCs, whereas 5-aza-2’-deoxycytidine, a DNA methylation inhibitor, decreased DCN mRNA expression and CGI-I methylation in aged bmMSCs, and ultimately enhanced the proliferation of serum-starved aged bmMSCs under IGF-I stimulation. Thus, IGF-IR could be the prime target of aging in down-regulating the IGF-I signaling of bmMSCs, where DCN could be a critical mediator.
- Published
- 2020
34. Loss of Atg7 causes chaotic nucleosome assembly of mouse bone marrow CD11b+Ly6G- myeloid cells
- Author
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Li Xu, Jiawei Qian, Lei Li, Yue Gu, Chen Zhao, Wen Wei, Yixuan Fang, Zhang Suping, Youjia Xu, Yanhua Du, Yuan Na, Cizhong Jiang, Ye Yuan, Lingjiang Zhu, and Jianrong Wang
- Subjects
Myeloid ,Nucleosome assembly ,ATG5 ,Population ,Bone Marrow Cells ,histone H3.1 ,Autophagy-Related Protein 7 ,nucleosome assembly ,Mice ,medicine ,Animals ,Antigens, Ly ,Myeloid Cells ,education ,Mice, Knockout ,education.field_of_study ,CD11b Antigen ,biology ,Chemistry ,Autophagy ,aging ,Cell Biology ,Cell biology ,Nucleosomes ,Haematopoiesis ,medicine.anatomical_structure ,Histone ,biology.protein ,Bone marrow ,Atg7 ,Research Paper - Abstract
Atg7, a critical component of autophagy machinery, is essential for counteracting hematopoietic aging. However, the non-autophagic role of Atg7 on hematopoietic cells remains fundamentally unclear. In this study, we found that loss of Atg7, but not Atg5, another autophagy-essential gene, in the hematopoietic system reduces CD11b myeloid cellularity including CD11b+Ly6G+ and CD11b+Ly6G- populations in mouse bone marrow. Surprisingly, Atg7 deletion causes abnormally accumulated histone H3.1 to be overwhelmingly trapped in the cytoplasm in the CD11b+Ly6G-, but not the CD11b+Ly6G+ compartment. RNA profiling revealed extensively chaotic expression of the genes required in nucleosome assembly. Functional assays further indicated upregulated aging markers in the CD11b+Ly6G- population. Therefore, our study suggests that Atg7 is essential for maintaining proper nucleosome assembly and limiting aging in the bone marrow CD11b+Ly6G- population.
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- 2020
35. miR-146b-5p regulates bone marrow mesenchymal stem cell differentiation by SIAH2/PPARγ in aplastic anemia children and benzene-induced aplastic anemia mouse model
- Author
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Xueju Xu, Yingchao Wang, Shufang Su, Huanhuan Li, Li Zeng, Linlin Wei, Hongliang You, Bai Li, Yu-Feng Liu, Yingqi Fang, Dao Wang, and Yuan Zhang
- Subjects
Male ,0301 basic medicine ,Adolescent ,Ubiquitin-Protein Ligases ,Bone Marrow Cells ,SIAH2 ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Ubiquitin ,medicine ,Animals ,Humans ,Luciferase ,Mir 146b ,Aplastic anemia ,Child ,Molecular Biology ,Cells, Cultured ,Adipogenesis ,biology ,Ubiquitination ,Anemia, Aplastic ,Nuclear Proteins ,Benzene ,Mesenchymal Stem Cells ,hemic and immune systems ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,PPAR gamma ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Case-Control Studies ,Child, Preschool ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Bone marrow ,Mesenchymal stem cell differentiation ,Signal Transduction ,Research Paper ,Developmental Biology - Abstract
This study aimed to reveal the mechanism of miR-146b-5p in the differentiation of bone marrow mesenchymal stem cells (BMSCs) derived from children with aplastic anemia (AA). Here, we found that miR-146b-5p was highly expressed in BMSCs from children with AA, and the BMSCs surface markers expressions in BMSCs derived from children with AA and the healthy controls exerted no significant differences. Besides, the overexpression of miR-146b-5p in normal human-derived BMSCs promoted the adipogenic differentiation of BMSCs. Furthermore, miR-146b-5p negatively regulated SIAH2 luciferase activity, and the interference with miR-146b-5p reduced the stability of PPARγ protein and inhibited SIAH2-mediated ubiquitination of PPARγ protein. Besides, the interference with miR-146b-5p was beneficial for ameliorating AA in a mouse model of AA. Overall, our results found that miR-146b-5p was highly expressed in BMSCs from children with AA, and our further studies indicated that miR-146b-5p improved AA via promoting SIAH2-mediated ubiquitination of PPARγ protein.
- Published
- 2020
36. Mesenchymal stem cells-derived exosomes ameliorate nucleus pulposus cells apoptosis via delivering miR-142-3p: therapeutic potential for intervertebral disc degenerative diseases
- Author
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Yuhui Shi, Pengcheng Shen, Ling Liu, Lifan Zhu, Huan Wang, and Huilin Yang
- Subjects
0301 basic medicine ,Nucleus Pulposus ,MAP Kinase Signaling System ,Interleukin-1beta ,Apoptosis ,Bone Marrow Cells ,Intervertebral Disc Degeneration ,Degeneration (medical) ,Biology ,Exosomes ,03 medical and health sciences ,0302 clinical medicine ,health services administration ,Back pain ,medicine ,Animals ,Molecular Biology ,Inflammation ,Base Sequence ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Intervertebral disc ,Cell Biology ,Microvesicles ,Mice, Inbred C57BL ,Transplantation ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,population characteristics ,medicine.symptom ,Nucleus ,Research Paper ,Developmental Biology - Abstract
Intervertebral disc degeneration (IDD) is the main cause of lower back pain (LBP), and puzzles massive individuals worldwide. Mesenchymal stem cells (MSCs) transplantation has been demonstrated to potentially ameliorate IDD progression, while the underlying mechanism has not been fully explained. Interleukin-1β (IL-1β) was used to induce nucleus pulposus cells (NPCs) injury. Bone marrow MSCs-derived exosomes were isolated using the super centrifugation method, and characterized using Transmission electron microscopy (TEM) and western blot. Cell viability was determined by MTT, while apoptosis was measured by Annexin-V staining using flow cytometry. miR-142-3fp and gene expressions were measured by real-time PCR. The protein expressions were determined by western blot. Herein, we found exosomes from bone marrow MSCs are circular vesicles, about 80 nm in diameter, and with robust expression of TSG101 and CD63, but without of Calnexin. MSCs exosomes alleviated NPCs apoptosis by reducing IL-1β-induced inflammatory cytokines secretion and MAPK signaling activation. Additionally, MSCs exosomes inhibited NPCs apoptosis and MAPK signaling by delivering miR-142-3p that targets mixed lineage kinase 3 (MLK3). Overexpression of MLK3 abolished the effects of MSCs exosomes on the inflammatory condition, cell apoptosis, and MAPK signaling activation in NPCs. The results confirmed that bone marrow MSCs-derived exosomes-packaged miR-142-3p alleviates NPCs injury through suppressing MAPK signaling by targeting MLK3. The work highlights the therapeutic effect of MSCs on IDD progression, and bone marrow MSCs exosomes might be apromising therapeutic strategy for IDD.
- Published
- 2020
37. Neuropeptide Y1 receptor antagonist promotes osteoporosis and microdamage repair and enhances osteogenic differentiation of bone marrow stem cells via cAMP/PKA/CREB pathway
- Author
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Yi Qin, Zhanchun Li, Yuan Wang, Weixin Xie, Fan Li, Jie Xiao, Xiaoying Chi, and Yi Han
- Subjects
Male ,Aging ,medicine.medical_specialty ,neuropeptide Y ,Osteoporosis ,Down-Regulation ,Bone Marrow Cells ,Arginine ,bone mcirodamage ,Bone remodeling ,Osteogenesis ,Internal medicine ,Cyclic AMP ,medicine ,Animals ,Humans ,Cyclic AMP Response Element-Binding Protein ,bone microstructure ,Aged ,biology ,Chemistry ,Bone Marrow Stem Cell ,Cell Differentiation ,Osteoblast ,X-Ray Microtomography ,Cell Biology ,medicine.disease ,osteoporosis ,humanities ,Rats ,Receptors, Neuropeptide Y ,Metabolic Bone Disorder ,Endocrinology ,medicine.anatomical_structure ,RANKL ,biology.protein ,Ovariectomized rat ,Female ,Bone marrow ,Research Paper ,bone marrow stromal cells - Abstract
Osteoporosis is a common metabolic bone disorder in the elderly population. The accumulation of bone microdamage is a critical factor of osteoporotic fracture. Neuropeptide Y (NPY) has been reported to regulated bone metabolism through Y1 receptor (Y1R). In this study the effects and mechanisms of Y1R antagonist on prevention for osteoporosis were characterized. In the clinical experiment, compared with osteoarthritis (OA), osteoporosis (OP) showed significant osteoporotic bone microstructure and accumulation of bone microdamage. NPY and Y1R immunoreactivity in bone were stronger in OP group, and were both correlated with bone volume fraction (BV/TV). In vivo experiment, Y1R antagonist significantly improved osteoporotic microstructure in the ovariectomized (OVX) rats. And Y1R antagonist promoted RUNX2, OPG and inhibit RANKL, MMP9 in bone marrow. In vitro cell culture experiment, NPY inhibited osteogenesis, elevated RANKL/OPG ratio and downregulated the expression of cAMP, p-PKAs and p-CREB in BMSCs, treated with Y1R antagonist or 8-Bromo-cAMP could inhibit the effects of NPY. Together, Y1R antagonist improved the bone microstructure and reduced bone microdamage in OVX rats. NPY-Y1R could inhibit osteoblast differentiation of BMSCs via cAMP/PKA/CREB pathway. Our findings highlight the regulation of NPY-Y1R in bone metabolism as a potential therapy strategy for the prevention of osteoporosis and osteoporotic fracture.
- Published
- 2020
38. Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss
- Author
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Seokho Kim, Mohammad Humayun Kabir, Kwang-Pyo Lee, Jae Sook Kang, Jae-Il Park, Ki Sun Kwon, Jin Hee Park, Seung Min Lee, Jaemin Lee, Shinyeong Ju, Yong Ryoul Yang, Yeo Jin Shin, Soo Young Lee, and Cheolju Lee
- Subjects
0301 basic medicine ,Male ,Proteomics ,medicine.medical_specialty ,Osteoclasts ,Bone Marrow Cells ,bone ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Osteoclast ,Internal medicine ,medicine ,Animals ,Scavenger receptor ,Receptor ,Cells, Cultured ,osteoclast differentiation ,Cartilage oligomeric matrix protein ,biology ,Chemistry ,Anthrax toxin receptor 2 ,Gene Expression Profiling ,Macrophages ,aging ,RANK Ligand ,NF-kappa B ,Cell Differentiation ,Cell Biology ,Cadherins ,Blood proteins ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,RANKL ,biology.protein ,Osteoporosis ,Female ,Signal transduction ,030217 neurology & neurosurgery ,Research Paper ,plasma proteins ,Signal Transduction - Abstract
The blood exhibits a dynamic flux of proteins that are secreted by the tissues and cells of the body. To identify novel aging-related circulating proteins, we compared the plasma proteomic profiles of young and old mice using tandem mass spectrometry. The expression of 134 proteins differed between young and old mice. We selected seven proteins that were expressed at higher levels in young mice, and confirmed their plasma expression in immunoassays. The plasma levels of anthrax toxin receptor 2 (ANTXR2), cadherin-13 (CDH-13), scavenger receptor cysteine-rich type 1 protein M130 (CD163), cartilage oligomeric matrix protein (COMP), Dickkopf-related protein 3 (DKK3), periostin, and secretogranin-1 were all confirmed to decrease with age. We then investigated whether any of the secreted proteins influenced bone metabolism and found that CDH-13 inhibited osteoclast differentiation. CDH 13 treatment suppressed the receptor activator of NF-κB ligand (RANKL) signaling pathway in bone marrow-derived macrophages, and intraperitoneal administration of CDH-13 delayed age-related bone loss in the femurs of aged mice. These findings suggest that low plasma CDH-13 expression in aged mice promotes aging-associated osteopenia by facilitating excessive osteoclast formation. Thus, CDH-13 could have therapeutic potential as a protein drug for the prevention of osteopenia.
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- 2020
39. Gadofullerene nanoparticles for robust treatment of aplastic anemia induced by chemotherapy drugs
- Author
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Chunru Wang, Wang Jia, Chen Zhou, Zihao Sun, Zhongpu Zhao, Mingming Zhen, Jie Li, Shuai Liu, Lei Li, and Chunli Bai
- Subjects
0301 basic medicine ,Myeloid ,aplastic anemia ,Medicine (miscellaneous) ,Bone Marrow Cells ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Erythropoiesis ,Aplastic anemia ,Antineoplastic Agents, Alkylating ,Busulfan ,Cyclophosphamide ,Erythropoietin ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,reactive oxygen species ,Mice, Inbred ICR ,Chemistry ,Anemia, Aplastic ,erythrocyte maturation ,Cell Differentiation ,gadofullerene nanoparticles ,Hematopoietic Stem Cells ,medicine.disease ,Disease Models, Animal ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Erythrocyte maturation ,030220 oncology & carcinogenesis ,Nanoparticles ,Female ,Fullerenes ,Bone marrow ,Stem cell ,Research Paper ,medicine.drug - Abstract
Aplastic anemia (AA) is characterized as hypoplasia of bone marrow hematopoietic cells and hematopenia of peripheral blood cells. Though the supplement of exogenous erythropoietin (EPO) has been clinically approved for AA treatment, the side-effects hinder its further application. Here a robust treatment for AA induced by chemotherapy drugs is explored using gadofullerene nanoparticles (GFNPs). Methods: The gadofullerene were modified with hydrogen peroxide under alkaline conditions to become the water-soluble nanoparticles (GFNPs). The physicochemical properties, in vitro chemical construction, stability, hydroxyl radical scavenging ability, in vitro cytotoxicity, antioxidant activity, in vivo treatment efficacy, therapeutic mechanism and biological distribution, metabolism, toxicity of GFNPs were examined. Results: GFNPs with great stability and high-efficiency antioxidant activity could observably increase the number of red blood cells (RBC) in the peripheral blood of AA mice and relieve the abnormal pathological state of bone marrow. The erythropoiesis mainly includes hemopoietic stem cells (HSCs) differentiation, erythrocyte development in bone marrow and erythrocyte maturation in peripheral blood. The positive control-EPO promotes erythropoiesis by regulating HSCs differentiation and erythrocyte development in bone marrow. Different from the anti-AA mechanism of EPO, GFNPs have little impact on both the differentiation of HSCs and the myeloid erythrocyte development, but notably improve the erythrocyte maturation. Besides, GFNPs can notably decrease the excessive reactive oxygen species (ROS) and inhibit apoptosis of hemocytes in blood. In addition, GFNPs are mostly excreted from the living body and cause no serious toxicity. Conclusion: Our work provides an insight into the advanced nanoparticles to powerfully treat AA through ameliorating the erythrocyte maturation during erythropoiesis.
- Published
- 2020
40. Transcriptome Profiling Reveals Distinct Phenotype of Human Bone Marrow Mesenchymal Stem Cell-derived Hepatocyte-like cells
- Author
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Qian Zhou, Yingyan Lu, Beibei Guo, Suwan Sun, Jing Jiang, Dongyan Shi, Jiaojiao Xin, Jun Li, Wenchao Ding, and Xingping Zhou
- Subjects
hepatocyte differentiation ,Bone Marrow Cells ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,mRNA sequencing ,RNA, Messenger ,Cells, Cultured ,mesenchymal stem cell ,Hepatocyte differentiation ,Gene Expression Profiling ,Mesenchymal stem cell ,Transdifferentiation ,Cell Differentiation ,Mesenchymal Stem Cells ,General Medicine ,Transplantation ,medicine.anatomical_structure ,MRNA Sequencing ,Hepatocytes ,Cancer research ,030211 gastroenterology & hepatology ,Bone marrow ,Stem cell ,Biomarkers ,Research Paper - Abstract
Background: Human bone marrow mesenchymal stem cell-derived hepatocyte-like cells (hBMSC-HLCs) are a promising alternative for primary human hepatocytes (HHs) for treating liver disease. However, the molecular characteristics of HLCs remain unclear. Here, we aimed to clarify the transcriptome characteristics of hBMSC-HLCs for future clinical application. Materials and Methods: hBMSCs were isolated from the bone marrow of healthy volunteers and differentiated into hepatocytes. mRNA sequencing was used in the transcriptome profiling of hBMSC-HLCs, with hBMSCs and HHs as controls. Results: hBMSC-HLCs exhibited a polygonal morphology, glycogen accumulation and albumin expression. A total of 630 upregulated and 1082 downregulated genes were observed in hBMSC-HLCs and HHs compared with undifferentiated hBMSCs. The upregulated genes were mainly involved in hepatic metabolism and inflammatory and immune responses. The downregulated genes were mainly associated with stem cell characteristics (multipotent differentiation, cell cycle regulation, etc.). Confirmatory qRT-PCR of 9 upregulated and 9 downregulated genes with log2 fold changes > 5 showed similar results. In vivo transdifferentiation of hBMSCs in pigs with fulminant hepatic failure confirmed the similarly upregulated expression of 5 hepatogenic genes (TDO2, HP, SERPINA3, LBP and SAA1), showing a 150-fold change in liver tissues at 7 days after hBMSC transplantation. These 5 genes mainly contributed to liver metabolism and inflammation. Conclusion: hBMSC-HLCs possess a hepatic transcriptome profile and express hepatic-specific genes in vitro and in vivo, which might be useful for future clinical applications. The five upregulated genes identified herein could be potential biomarkers for the characterization of hBMSC-HLCs.
- Published
- 2020
41. Differential Gene Expression between Limbal Niche Progenitors and Bone Marrow Derived Mesenchymal Stem Cells
- Author
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Yingting Zhu, Wei Wang, Guigang Li, Sean Tighe, Yuan Zhang, Ling-Juan Xu, Menglin Jiang, Xinyu Li, and Shen Li
- Subjects
Collagen Type IV ,FZD1 ,gene chip ,Bone Marrow Cells ,Limbus Corneae ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Humans ,CD90 ,Stem Cell Niche ,Progenitor cell ,Wnt Signaling Pathway ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Matrigel ,Gene Expression Profiling ,Mesenchymal stem cell ,Wnt signaling pathway ,Cell Differentiation ,Mesenchymal Stem Cells ,General Medicine ,Embryonic stem cell ,Culture Media ,Cell biology ,Gene Expression Regulation ,030211 gastroenterology & hepatology ,Laminin ,LNC ,BMMSC ,Research Paper - Abstract
Purpose: To compare the difference in gene expression between human limbal niche cells (LNC) and bone marrow derived mesenchymal stem cells (BMMSC). Methods: LNC were isolated by collagenase and expanded in modified embryonic stem cell medium (MESCM) on a Matrigel coated plastic plate. Cell diameters were measured with Image J software. Relative gene expression levels between LNC and BMMSC were compared using Affymetrix Human Primer View Gene Expression Array. A subset of differentially expressed genes was verified by RT-qPCR. The protein level of LAMA1 and COL4A1 was confirmed by Western blot and immunostaining. Results: The average diameter of LNC was 10.2±2.4 μm, which was significantly smaller than that of BMMSC (14 ±3.4 μm) (p
- Published
- 2020
42. CXCR4/TGF-β1 mediated self-differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and promoted colorectal carcinoma development
- Author
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Hao-Xiang Tan, Zhongcheng Huang, Yu Liu, Zhi-Gang Xiao, Zhixue Fang, and Tao Huang
- Subjects
0301 basic medicine ,Receptors, CXCR4 ,Cancer Research ,Carcinoma associated fibroblasts ,Colorectal cancer ,Mice, Nude ,Apoptosis ,Bone Marrow Cells ,CXCR4 ,Transforming Growth Factor beta1 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Cell Movement ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Neoplasm Invasiveness ,Cell Proliferation ,Pharmacology ,Tumor microenvironment ,business.industry ,Liver Neoplasms ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,medicine.disease ,Xenograft Model Antitumor Assays ,Coculture Techniques ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,sense organs ,Colorectal Neoplasms ,business ,Self differentiation ,Research Paper ,Transforming growth factor - Abstract
Background: Tumor microenvironment (TME) is a crucial part of tumor hallmarks. Mesenchymal stem cells (MSCs), important components of TME, are the main source of Carcinoma-associated fibroblasts (CAFs), but the mechanism of transformation regulation is still unclear. Transforming growth factor-β1 (TGF-β1), chemokine Stromal cell-derived factor-1 (SDF-1) and its endogenous receptor CXCR4 may play important roles during this process. Methods: Co-culture technique was used to explore the effects of MSCs on the proliferation, migration and invasion of colorectal carcinoma (CRC) cells and how they induced MSCs to differentiate into CAFs. The expression of α-SMA, Vimentin, S100A4 and FAP were detected as CAFs markers. Inhibitors AMD3100 and cyclophosphamide (Cy) were pre-treated in MSCs to verify the functions of CXCR4/TGF-β1. Finally, the xenograft models in nude mice were generated to further verify this process in vivo. Results: MSCs promoted the CRCs proliferation, invasion and migration, and induced SDF-1 expression and secretion, which dramatically up-regulated CXCR4 and TGF-β1 expression in MSCs. The levels of CAFs markers elevated in MSCs, indicating CAFs differentiation occurred in MSCs. AMD3100 and Cy treatment significantly blocked this differentiation process of MSCs by suppressing CXCR4 expression and TGF-β1 secretion. In vivo xenograft experiments also demonstrated that MSCs promoted differentiation into CAFs through CXCR4/TGF-β1 signaling in either primary tumor tissues or hepatic metastatic tissues of CRC. Conclusion: Our studies have revealed the essential role of CXCR4/TGF-β1 axis playing in the transformation of tumor microenvironment by mediating MSCs differentiation into CAFs, promoting CRCs growth and metastasis.
- Published
- 2019
43. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis
- Author
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Ting Wen, Yang Junxiao, Pengfei Lei, and Yang Xucheng
- Subjects
Aging ,Bone Marrow Cells ,Exosomes ,Exosome ,Bone and Bones ,Sincalide ,osteogenesis ,Mice ,microRNA ,medicine ,exosome ,Animals ,Humans ,Gene silencing ,MALAT1 ,Cells, Cultured ,Osteoblasts ,Chemistry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Osteoblast ,X-Ray Microtomography ,Cell Biology ,osteoporosis ,Coculture Techniques ,Microvesicles ,Cell biology ,MicroRNAs ,medicine.anatomical_structure ,bone marrow-derived mesenchymal stem cells ,Alkaline phosphatase ,RNA, Long Noncoding ,Bone marrow ,Research Paper - Abstract
Long non-coding RNAs (lncRNAs) have emerged as promising novel modulators during osteogenesis in mesenchymal stem cells (MSCs). Enhanced SATB2 has been demonstrated to promote osteogenic differentiation of bone marrow-derived mesenchymal stem cells (hBMSCs) in patients with osteonecrosis. Preliminary bioinformatic analysis identified putative binding sites between microRNA-34c (miR-34c) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) or miR-34c and SATB2 3’UTR. Thus, the current study aimed to clarify the potential functional relevance of MALAT1-containing exosomes from BMSCs in osteoporosis. The extracted exosomes from primary BMSCs were co-cultured with human osteoblasts (hFOB1.19), followed by evaluation of the hFOB1.19 cell proliferation, alkaline phosphatase (ALP) activity and mineralized nodules. The obtained findings indicated that BMSC-Exos promoted the expression of SATB2 in osteoblasts, and SATB2 silencing reduced the ALP activity of osteoblasts and mineralized nodules. MALAT1 acted as a sponge of miR-34c to promote the expression of SATB2. Additionally, BMSCs-derived exosomal MALAT1 promoted osteoblast activity. Moreover, in vivo experiments indicated that miR-34c reversed the effect of MALAT1, and SATB2 reversed the effect of miR-34c in ovariectomized mice. Taken together, this study demonstrates that BMSCs-derived exosomal MALAT1 enhances osteoblast activity in osteoporotic mice by mediating the miR-34c/SATB2 axis.
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- 2019
44. Optogenetic control of mesenchymal cell fate towards precise bone regeneration
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Chenyu Guan, Baicheng Bao, Delan Huang, Zhicai Feng, Weicai Wang, Junqi Ling, Bin Cai, Chen Zhou, Jianhan Ren, and Runze Li
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0301 basic medicine ,Bone Regeneration ,Medicine (miscellaneous) ,Bone Morphogenetic Protein 2 ,Bone Marrow Cells ,02 engineering and technology ,Optogenetics ,Cell fate determination ,Biology ,Regenerative Medicine ,Regenerative medicine ,Bone morphogenetic protein 2 ,03 medical and health sciences ,gene expression control ,Osteogenesis ,Transforming Growth Factor beta ,proliferation and differentiation ,Animals ,Humans ,Mesenchymal stem cell proliferation ,Bone regeneration ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Tissue Scaffolds ,Regeneration (biology) ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,021001 nanoscience & nanotechnology ,bone tissue regeneration ,Recombinant Proteins ,Cell biology ,Rats ,030104 developmental biology ,HEK293 Cells ,Gene Expression Regulation ,0210 nano-technology ,Research Paper - Abstract
Rationale: Spatial-temporal control of cell fate in vivo is of great importance for regenerative medicine. Currently, there remain no practical strategies to tune cell-fate spatial-temporally. Optogenetics is a biological technique that widely used to control cell activity in genetically defined neurons in a spatiotemporal-specific manner by light. In this study, optogenetics was repurposed for precise bone tissue regeneration. Methods: Lhx8 and BMP2 genes, which are considered as the master genes for mesenchymal stem cell proliferation and differentiation respectively, were recombined into a customized optogenetic control system. In the system, Lhx8 was constitutively expressed, while BMP2 together with shLhx8 expression was driven by blue light. Results: As expected, blue light induced BMP2 expression and inactivated Lhx8 expression in cells infected with the optogenetic control system. Optogenetic control of BMP2 and Lhx8 expression inversely regulates MSC fate in vitro. By animal study, we found that blue light could fine-tune the regeneration in vivo. Blue light illumination significantly promotes bone regeneration when the scaffold was loaded with MSCs infected with adeno-Lhx8, GI-Gal4DBD, LOV-VP16, and BMP2-shLhx8. Conclusions: Together, our study revealed that optogenetic control of the master genes for mesenchymal stem cell proliferation and differentiation would be such a candidate strategy for precise regenerative medicine.
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- 2019
45. Alexander Friedenstein, Mesenchymal Stem Cells, Shifting Paradigms and Euphemisms.
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Phinney, Donald G.
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MESENCHYMAL stem cells ,BONE marrow cells ,PROGENITOR cells ,EUPHEMISM ,STROMAL cells - Abstract
Six decades ago, Friedenstein and coworkers published a series of seminal papers identifying a cell population in bone marrow with osteogenic potential, now referred to as mesenchymal stem cells (MSCs). This work was also instrumental in establishing the identity of hematopoietic stem cell and the identification of skeletal stem/progenitor cell (SSPC) populations in various skeletal compartments. In recognition of the centenary year of Friedenstein's birth, I review key aspects of his work and discuss the evolving concept of the MSC and its various euphemisms indorsed by changing paradigms in the field. I also discuss the recent emphasis on MSC stromal quality attributes and how emerging data demonstrating a mechanistic link between stromal and stem/progenitor functions bring renewed relevance to Friedenstein's contributions and much needed unity to the field. [ABSTRACT FROM AUTHOR]
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- 2024
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46. Highly accurate differentiation of bone marrow cell morphologies using deep neural networks on a large image data set
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Christian Münzenmayer, Carsten Marr, Christian Matek, Torsten Haferlach, Sebastian Krappe, and Publica
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Computer science ,Immunology ,Plenary Paper ,Bone Marrow Cells ,Cell morphology ,Biochemistry ,Convolutional neural network ,Image (mathematics) ,Image Processing, Computer-Assisted ,Humans ,Microscopy ,business.industry ,Computers ,Deep learning ,Pattern recognition ,Cell Differentiation ,Cell Biology ,Hematology ,Hematologic Diseases ,Data set ,Feature (computer vision) ,Deep neural networks ,Artificial intelligence ,Neural Networks, Computer ,business ,Precision and recall - Abstract
Artificial intelligence (AI) and machine learning algorithms are changing many facets of our lives and have great potential for disease diagnosis. In this Plenary Paper, Matek et al describe training a convolutional neural network model using 171 374 bone marrow cytology images from 945 patients with various hematological diseases before validating its accuracy in classifying single cells in an independent set of 627 images. The system can automatically classify 22 classes of bone marrow leukocytes, and with further improvements, it may bring AI-aided diagnosis of bone marrow biopsy specimens closer to fruition., Key Points A data set of >170 000 microscopic images allows training neural networks for identification of BM cells with high accuracy.Neural networks outperform a feature-based approach to BM cell classification and can be analyzed with explainability and feature embedding methods., Visual Abstract, Biomedical applications of deep learning algorithms rely on large expert annotated data sets. The classification of bone marrow (BM) cell cytomorphology, an important cornerstone of hematological diagnosis, is still done manually thousands of times every day because of a lack of data sets and trained models. We applied convolutional neural networks (CNNs) to a large data set of 171 374 microscopic cytological images taken from BM smears from 945 patients diagnosed with a variety of hematological diseases. The data set is the largest expert-annotated pool of BM cytology images available in the literature. It allows us to train high-quality classifiers of leukocyte cytomorphology that identify a wide range of diagnostically relevant cell species with high precision and recall. Our CNNs outcompete previous feature-based approaches and provide a proof-of-concept for the classification problem of single BM cells. This study is a step toward automated evaluation of BM cell morphology using state-of-the-art image-classification algorithms. The underlying data set represents an educational resource, as well as a reference for future artificial intelligence–based approaches to BM cytomorphology.
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- 2020
47. The effect of ionising radiation on the phenotype of bone marrow-derived extracellular vesicles
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Zoltán Varga, Katalin Lumniczky, Lilla Antal, Dávid Kis, Bálint Jezsó, Eszter Persa, Judith Mihály, Géza Sáfrány, Attila Bóta, Enikő Kis, Tünde Szatmári, Ilona Barbara Csordás, and Rita Hargitai
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Male ,Cell ,Bone Marrow Cells ,030204 cardiovascular system & hematology ,Flow cytometry ,03 medical and health sciences ,Extracellular Vesicles ,Mice ,0302 clinical medicine ,Bone Marrow ,Radiation, Ionizing ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Secretion ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,biology ,Chemistry ,Integrin beta1 ,CD44 ,CD29 ,General Medicine ,Flow Cytometry ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,Hyaluronan Receptors ,Phenotype ,Advances in radiation biology – Highlights from 16th ICRR special feature: Full Paper ,biology.protein ,Mice, Inbred CBA ,Bone marrow ,Stem cell ,Whole-Body Irradiation - Abstract
Objectives: Ionising radiation-induced alterations affecting intercellular communication in the bone marrow (BM) contribute to the development of haematological pathologies. Extracellular vesicles (EVs), which are membrane-coated particles released by cells, have important roles in intercellular signalling in the BM. Our objective was to investigate the effects of ionising radiation on the phenotype of BM-derived EVs of total-body irradiated mice. Methods: CBA mice were irradiated with 0.1 Gy or 3 Gy X-rays. BM was isolated from the femur and tibia 24 h after irradiation. EVs were isolated from the BM supernatant. The phenotype of BM cells and EVs was analysed by flow cytometry. Results: The mean size of BM-derived EVs was below 300 nm and was not altered by ionising radiation. Their phenotype was very heterogeneous with EVs carrying either CD29 or CD44 integrins representing the major fraction. High-dose ionising radiation induced a strong rearrangement in the pool of BM-derived EVs which were markedly different from BM cell pool changes. The proportion of CD29 and CD44 integrin-harbouring EVs significantly decreased and the relative proportion of EVs with haematopoietic stem cell or lymphoid progenitor markers increased. Low-dose irradiation had limited effect on EV secretion. Conclusions: Ionising radiation induced selective changes in the secretion of EVs by the different BM cell subpopulations. Advances in knowledge: The novelty of the paper consists of performing a detailed phenotyping of BM-derived EVs after in vivo irradiation of mice.
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- 2020
48. Design, Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome
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Baldwin, Alex G., Tapia, Victor S., Swanton, Tessa, White, Claire S., Beswick, James A., Brough, David, and Freeman, Sally
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Boron Compounds ,Lipopolysaccharides ,integumentary system ,Full Paper ,Inflammasomes ,Macrophages ,Interleukin-1beta ,Anti-Inflammatory Agents ,Bone Marrow Cells ,Full Papers ,NLRP3 inflammasome ,Mice ,Structure-Activity Relationship ,inflammation ,Drug Design ,oxazaborines ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,structure–activity relationships ,boron ,Cells, Cultured - Abstract
The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host‐derived sterile molecules leads to the intracellular activation of caspase‐1, processing of the pro‐inflammatory cytokines interleukin‐1β (IL‐1β)/IL‐18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non‐communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors. Structure–activity relationships (SAR) show that 4‐fluoro substituents on the phenyl rings retain NLRP3 inhibitory activity, whereas more steric and lipophilic substituents diminish activity. Loss of inhibitory activity is also observed if the CCl3 group on the oxazaborine ring is replaced by a CF3 group. These findings provide additional understanding of the NBC series and will aid in the development of these NLRP3 inhibitors as tool compounds or therapeutic candidates for sterile inflammatory diseases.
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- 2018
49. Effect of Systemic Administration of Granulocyte Colony-Stimulating Factor on a Chronic Partial-Thickness Cartilage Defect in a Rabbit Knee Joint
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Takahisa Sasho, Seiji Kimura, Masashi Shinohara, Yuya Ogawa, Satoshi Yamaguchi, Shotaro Watanabe, Aya Sadamasu, Seiji Ohtori, Hiroaki Hosokawa, Ryuichiro Akagi, Manato Horii, Yukio Mikami, and Yoshimasa Ono
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Cartilage, Articular ,Pathology ,medicine.medical_specialty ,Knee Joint ,education ,Biomedical Engineering ,Physical Therapy, Sports Therapy and Rehabilitation ,Stimulation ,Bone Marrow Cells ,Granulocyte Colony-Stimulating Factor ,medicine ,Immunology and Allergy ,Animals ,Clinical Research papers ,business.industry ,Regeneration (biology) ,Cartilage ,digestive, oral, and skin physiology ,Granulocyte colony-stimulating factor ,stomatognathic diseases ,Knee pain ,medicine.anatomical_structure ,Systemic administration ,Bone marrow ,Rabbits ,medicine.symptom ,business ,Cartilage Diseases - Abstract
Objective Cartilage lesions in the knee joint can lead to joint mechanics changes and cause knee pain. Bone marrow stimulation (BMS) promotes cartilage regeneration by perforating the subchondral bone just below the injury and inducing bone marrow cells. This study aimed to investigate whether systemic administration of granulocyte colony-stimulating factor (G-CSF) with BMS improves repair of chronic partial-thickness cartilage defects (PTCDs). Design Eighteen 6-month-old New Zealand white rabbits were divided into 3 groups: control (C, n = 6), BMS alone ( n = 6), and BMS + G-CSF ( n = 6). Partial cartilage defects with 5 mm diameter were created in the trochlear region of both knees; after 4 weeks, the BMS alone and BMS + G-CSF groups underwent BMS; G-CSF (50 µg/kg) or saline was administered subcutaneously for 5 days starting from 3 days before BMS. At 8 and 16 weeks after cartilage defect creation, the area of cartilage defects was macroscopically and histologically evaluated. Results International Cartilage Repair Society (ICRS) grades for macroscopic assessment were 0, 0.7, and 0.7 at 8 weeks and 0, 1.2, and 1.3 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. Wakitani scores for histological assessment were 9.8, 8.7, and 8.2 at 8 weeks and 9.5, 9, and 8.2 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. The BMS + G-CSF group showed significantly more repair than the C group, but there was no difference from the BMS group. Conclusions The effect of BMS and G-CSF on chronic PTCDs in mature rabbit knees was limited.
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- 2021
50. 3D-bioprinting a genetically inspired cartilage scaffold with GDF5-conjugated BMSC-laden hydrogel and polymer for cartilage repair
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Zanjin Zhai, Ye Sun, Kerong Dai, Wenbo Jiang, and Yongqing You
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0301 basic medicine ,musculoskeletal diseases ,Cartilage, Articular ,Scaffold ,Pathology ,medicine.medical_specialty ,Medicine (miscellaneous) ,Mice, Nude ,Bone Marrow Cells ,02 engineering and technology ,Biology ,GDF5 ,03 medical and health sciences ,Mice ,Tissue engineering ,Cell Movement ,Growth Differentiation Factor 5 ,Articular cartilage repair ,medicine ,3d-bioprinting ,Animals ,Hip Dislocation ,Humans ,genetics ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Bone Marrow Transplantation ,Tissue Engineering ,Tissue Scaffolds ,Regeneration (biology) ,Cartilage ,Stem Cells ,Bioprinting ,Hydrogels ,021001 nanoscience & nanotechnology ,Chondrogenesis ,joint dysplasia ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,Printing, Three-Dimensional ,Rabbits ,hydrogel ,0210 nano-technology ,Research Paper ,Genome-Wide Association Study ,Stem Cell Transplantation - Abstract
Rationale: Articular cartilage injury is extremely common in congenital joint dysplasia patients. Genetic studies have identified Growth differentiation factor 5 (GDF5) as a shared gene in joint dysplasia and OA progression across different populations. However, few studies have employed GDF5 in biological regeneration for articular cartilage repair. Methods & Results: In the present study, we report identified genetic association between GDF5 loci and hip joint dysplasia with genome-wide association study (GWAS). GWAS and replication studies in separate populations achieved significant signals for GDF5 loci. GDF5 expression was dysregulated with allelic differences in hip cartilage of DDH and upregulated in the repaired cartilage in a rabbit cartilage defect model. GDF5 in vitro enhanced chondrogenesis and migration of bone marrow stem cells (BMSCs), GDF5 was tested in ectopic cartilage generation with BMSCs by GDF5 in nude mice in vivo. Genetically inspired, we further generated functional knee articular cartilage construct for cartilage repair by 3d-bioprinting a GDF5-conjugated BMSC-laden scaffold. GDF5-conjugated scaffold showed better cartilage repairing effects compared to control. Meanwhile, transplantation of the 3D-bioprinted GDF5-conjugated BMSC-laden scaffold in rabbit knees conferred long-term chondroprotection. Conclusions: In conclusion, we report identified genetic association between GDF5 and DDH with combined GWAS and replications, which further inspired us to generate a ready-to-implant GDF5-conjugated BMSC-laden scaffold with one-step 3d-bioprinting for cartilage repair.
- Published
- 2019
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