175 results on '"HEMATOPOIETIC STEM-CELLS"'
Search Results
2. Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond.
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Ahmed, Wesam and Van Etten, Richard A
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Chronic Myelogenous Leukemia ,Minimal Residual Disease ,Complete Molecular Response ,Hematopoietic Stem-Cells ,Complete Cytogenetic Response ,Hedgehog Pathway Activation ,P210 Multipeptide Vaccine ,Bcr-Abl Expression ,Imatinib Mesylate ,Beta-Catenin - Abstract
In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.
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- 2013
3. Cell Lineages and the Logic of Proliferative Control
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Lander, Arthur D, Gokoffski, Kimberly K, Wan, Frederic Y. M, Nie, Qing, Calof, Anne L, and Stevens, Charles F
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mouse olfactory epithelium ,hematopoietic stem-cells ,fibroblast-growth-factor ,receptor neuron lineage ,progenitor cells ,in-vitro ,signaling pathways ,morphogen gradient ,self-renewal ,terminal differentiation - Abstract
It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors ("chalones") may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives-what, precisely, is being controlled, and to what degree-and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE-the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue-fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules-such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator-may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.
- Published
- 2009
4. Bone Marrow Harbors a Unique Population of Dendritic Cells with the Potential to Boost Neutrophil Formation upon Exposure to Fungal Antigen
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Marieke Goedhart, Edith Slot, Maria F. Pascutti, Sulima Geerman, Timo Rademakers, Benjamin Nota, Stephan Huveneers, Jaap D. van Buul, Katherine C. MacNamara, Carlijn Voermans, Martijn A. Nolte, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, AII - Inflammatory diseases, and Landsteiner Laboratory
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RNA, Messenger/genetics ,Macrophage-1 Antigen/metabolism ,Neutrophils ,C-Type/genetics ,Inbred C57BL ,Mice ,C/EBP-BETA ,Lectins ,Granulocyte Colony-Stimulating Factor ,80 and over ,Biology (General) ,Aged, 80 and over ,BETA-GLUCAN RECEPTOR ,granulopoiesis ,hemic and immune systems ,General Medicine ,COLONY-STIMULATING FACTOR ,Middle Aged ,Zymosan/metabolism ,dectin-1 ,dendritic cells ,bone marrow ,hematopoiesis ,fungal infection ,zymosan ,Granulocyte Colony-Stimulating Factor/metabolism ,Antigens, Fungal ,QH301-705.5 ,Antigens, Fungal/immunology ,Macrophage-1 Antigen ,Lectins, C-Type/genetics ,Bone Marrow Cells ,G-CSF ,Article ,Fungal/immunology ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,Lectins, C-Type ,RNA, Messenger ,Antigens ,Aged ,Inflammation ,TRANSPLANTATION ,Gene Expression Profiling ,Neutrophils/immunology ,RECOGNITION ,Mice, Inbred C57BL ,Gene Expression Regulation ,Dendritic Cells/immunology ,CLINICAL-PRACTICE ,RNA ,Messenger/genetics ,Bone Marrow Cells/immunology ,GRANULOCYTE ,Inflammation/pathology - Abstract
Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.
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- 2022
5. Raman microspectroscopy reveals unsaturation heterogeneity at the lipid droplet level and validates an in vitro model of bone marrow adipocyte subtypes
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Josefine Tratwal, Guillaume Falgayrac, Alexandrine During, Nicolas Bertheaume, Charles Bataclan, Daniel N. Tavakol, Vasco Campos, Ludovic Duponchel, George Q. Daley, Guillaume Penel, Christophe Chauveau, and Olaia Naveiras
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unsaturation (fatty acid) ,bone marrow stromal cell (bmsc) ,spectroscopy ,regulated bone marrow adiposity ,deficiency ,single-cell ,constitutive bone marrow adiposity ,hematopoietic stem-cells ,adipose-tissue ,metabolic-regulation ,op9 cell ,lipid droplet diameter ,stroma ,fatty-acid-composition ,yellow marrow ,fatty acid ,mobilization ,stromal cells - Abstract
Bone marrow adipocytes (BMAds) constitute the most abundant stromal component of adult human bone marrow. Two subtypes of BMAds have been described, the more labile regulated adipocytes (rBMAds) and the more stable constitutive adipocytes (cBMAds), which develop earlier and are more resilient to environmental and metabolic disruptions. In vivo, rBMAds are enriched in saturated fatty acids, contain smaller lipid droplets (LDs) and more readily provide hematopoietic support than their cBMAd counterparts. Mouse models have been used for BMAds research, but isolation of primary BMAds presents many challenges, and thus in vitro models remain the current standard to study nuances of adipocyte differentiation. No in vitro model has yet been described for the study of rBMAds/cBMAds.Here, we present an in vitro model of BM adipogenesis with differential rBMAd and cBMAd-like characteristics. We used OP9 BM stromal cells derived from a (C57BL/6xC3H)F2-op/op mouse, which have been extensively characterized as feeder layer for hematopoiesis research. We observed similar canonical adipogenesis transcriptional signatures for spontaneously-differentiated (sOP9) and induced (iOP9) cultures, while fatty acid composition and desaturase expression of Scd1 and Fads2 differed at the population level. To resolve differences at the single adipocyte level we tested Raman microspectroscopy and show it constitutes a high-resolution method for studying adipogenesis in vitro in a label-free manner, with resolution to individual LDs. We found sOP9 adipocytes have lower unsaturation ratios, smaller LDs and higher hematopoietic support than iOP9 adipocytes, thus functionally resembling rBMAds, while iOP9 more closely resembled cBMAds. Validation in human primary samples confirmed a higher unsaturation ratio for lipids extracted from stable cBMAd-rich sites (femoral head upon hip-replacement surgery) versus labile rBMAds (iliac crest after chemotherapy). As a result, the 16:1/16:0 fatty acid unsaturation ratio, which was already shown to discriminate BMAd subtypes in rabbit and rat marrow, was validated to discriminate cBMAds from rBMAd in both the OP9 model in vitro system and in human samples. We expect our model will be useful for cBMAd and rBMAd studies, particularly where isolation of primary BMAds is a limiting step.
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- 2022
6. Tipping the balance between erythroid cell differentiation and induction of anemia in response to the inflammatory pathology associated with chronic trypanosome infections
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Hang Thi Thu Nguyen, Magdalena Radwanska, Stefan Magez, Department of Bio-engineering Sciences, and Cellular and Molecular Immunology
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Trypanosoma ,Immunology ,Trypanosomiasis/metabolism ,MACROPHAGE ACTIVATION ,Mice ,Erythroid Cells ,Trypanosomiasis ,Medicine and Health Sciences ,L-LACTATE ,immunopathology ,Immunology and Allergy ,Animals ,HEMATOPOIETIC STEM-CELLS ,Erythropoiesis ,NITRIC-OXIDE SYNTHASE ,tissue resident macrophages ,AFRICAN TRYPANOSOMES ,INTERFERON-GAMMA ,Trypanosomosis ,Biology and Life Sciences ,extramedullary erythropoiesis ,NECROSIS-FACTOR-ALPHA ,BRUCEI ,Anemia ,Cell Differentiation ,IN-VITRO ,Erythropoiesis/physiology ,Erythroid Cells/pathology ,EVANSI INFECTION ,lactic acidosis ,Anemia/etiology - Abstract
Infection caused by extracellular single-celled trypanosomes triggers a lethal chronic wasting disease in livestock and game animals. Through screening of 10Trypanosoma evansifield isolates, exhibiting different levels of virulence in mice, the current study identifies an experimental disease model in which infection can last well over 100 days, mimicking the major features of chronic animal trypanosomosis. In this model, despite the well-controlled parasitemia, infection is hallmarked by severe trypanosomosis-associated pathology. An in-depth scRNA-seq analysis of the latter revealed the complexity of the spleen macrophage activation status, highlighting the crucial role of tissue resident macrophages (TRMs) in regulating splenic extramedullary erythropoiesis. These new data show that in the field of experimental trypanosomosis, macrophage activation profiles have so far been oversimplified into a bi-polar paradigm (M1 vs M2). Interestingly, TRMs exert a double-sided effect on erythroid cells. On one hand, these cells express an erythrophagocytosis associated signature. On another hand, TRMs show high levels ofVcam1expression, known to support their interaction with hematopoietic stem and progenitor cells (HSPCs). During chronic infection, the latter exhibit upregulated expression ofKlf1,E2f8, andGfi1bgenes, involved in erythroid differentiation and extramedullary erythropoiesis. This process gives rise to differentiation of stem cells to BFU-e/CFU-e, Pro E, and Baso E subpopulations. However, infection truncates progressing differentiation at the orthochromatic erythrocytes level, as demonstrated by scRNAseq and flow cytometry. As such, these cells are unable to pass to the reticulocyte stage, resulting in reduced number of mature circulating RBCs and the occurrence of chronic anemia. The physiological consequence of these events is the prolonged poor delivery of oxygen to various tissues, triggering lactic acid acidosis and the catabolic breakdown of muscle tissue, reminiscent of the wasting syndrome that is characteristic for the lethal stage of animal trypanosomosis.
- Published
- 2022
7. Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia
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Tiina Kelkka, Mikko Tyster, Sofie Lundgren, Xingmin Feng, Cassandra Kerr, Kohei Hosokawa, Jani Huuhtanen, Mikko Keränen, Bhavisha Patel, Toru Kawakami, Yuka Maeda, Otso Nieminen, Tiina Kasanen, Pasi Aronen, Bhagwan Yadav, Hanna Rajala, Hideyuki Nakazawa, Taina Jaatinen, Eva Hellström-Lindberg, Seishi Ogawa, Fumihiro Ishida, Hiroyoshi Nishikawa, Shinji Nakao, Jaroslaw Maciejewski, Neal S. Young, Satu Mustjoki, Medicum, TRIMM - Translational Immunology Research Program, Department of Clinical Chemistry and Hematology, University of Helsinki, Hematologian yksikkö, HUS Comprehensive Cancer Center, Faculty Common Matters (Faculty of Medicine), Faculty of Medicine, HUS Helsinki and Uusimaa Hospital District, Clinicum, and Digital Precision Cancer Medicine (iCAN)
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Adult ,Cancer Research ,IDENTIFICATION ,Pancytopenia ,3122 Cancers ,Anemia, Aplastic ,Hematology ,ASSOCIATION ,DIAGNOSIS ,Oncology ,Cyclooxygenase 2 ,PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA ,CARBONIC-ANHYDRASE ,ANTIBODIES ,Humans ,HEMATOPOIETIC STEM-CELLS ,IMMUNOSUPPRESSIVE THERAPY ,MEGAKARYOPOIESIS ,Biomarkers ,Autoantibodies ,HLA-DRB1 Chains ,MYELODYSPLASTIC SYNDROME - Abstract
In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab). In total, 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the >40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable disease biomarker.
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- 2022
8. Gastruloids as in vitro models of embryonic blood development with spatial and temporal resolution
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Giuliana, Rossi, Sonja, Giger, Tania, Hübscher, and Matthias P, Lutolf
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Mammals ,Multidisciplinary ,Gene Expression Profiling ,commitment ,Embryonic Development ,Gastrula ,progenitor cells ,Embryo, Mammalian ,hematopoietic stem-cells ,Organoids ,Mice ,endothelial-cells ,specification ,ontogeny ,generation ,definitive hematopoiesis ,expression ,origin ,Animals - Abstract
Gastruloids are three-dimensional embryonic organoids that reproduce key features of early mammalian development in vitro with unique scalability, accessibility, and spatiotemporal similarity to real embryos. Recently, we adapted the gastruloid culture conditions to promote cardiovascular development. In this work, we extended these conditions to capture features of embryonic blood development through a combination of immunophenotyping, detailed transcriptomics analysis, and identification of blood stem/progenitor cell potency. We uncovered the emergence of blood progenitor and erythroid-like cell populations in late gastruloids and showed the multipotent clonogenic capacity of these cells, both in vitro and after transplantation into irradiated mice. We also identified the spatial localization near a vessel-like plexus in the anterior portion of gastruloids with similarities to the emergence of blood stem cells in the mouse embryo. These results highlight the potential and applicability of gastruloids to the in vitro study of complex processes in embryonic blood development with spatiotemporal fidelity.
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- 2022
9. HIF1/2-exerted control over glycolytic gene expression is not functionally relevant for glycolysis in human leukemic stem/progenitor cells
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Andre B. Mulder, Maurien Pruis, Edo Vellenga, Albertus T. J. Wierenga, Joost H.A. Martens, Ulrich L. Günther, Annet Z. Brouwers-Vos, Jan Jacob Schuringa, Alan Cunningham, Nuria Vilaplana Lopera, Ayşegül Erdem, Stem Cell Aging Leukemia and Lymphoma (SALL), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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0301 basic medicine ,BONE-MARROW ,Human hematopoietic stem cells ,HIF-BINDING ,HIF-1-ALPHA ,lcsh:RC254-282 ,OXYGEN ,Transcriptome ,03 medical and health sciences ,INDUCED AUTOPHAGY ,0302 clinical medicine ,HYPOXIA-INDUCIBLE FACTORS ,Acute myeloid leukemia (AML) ,HEMATOPOIETIC STEM-CELLS ,Progenitor cell ,Hypoxia ,BCR-ABL ,Glutaminolysis ,Chemistry ,Research ,Chromatin binding ,NICHE ,HIF-2-ALPHA ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Chromatin ,Cell biology ,Transplantation ,Psychiatry and Mental health ,Haematopoiesis ,030104 developmental biology ,Hypoxia-inducible factors ,030220 oncology & carcinogenesis ,Hypoxia induced factors (HIFs) ,METABOLIC-REGULATION ,Glycolysis - Abstract
Background Hypoxia-inducible factors (HIF)1 and 2 are transcription factors that regulate the homeostatic response to low oxygen conditions. Since data related to the importance of HIF1 and 2 in hematopoietic stem and progenitors is conflicting, we investigated the chromatin binding profiles of HIF1 and HIF2 and linked that to transcriptional networks and the cellular metabolic state. Methods Genome-wide ChIPseq and ChIP-PCR experiments were performed to identify HIF1 and HIF2 binding sites in human acute myeloid leukemia (AML) cells and healthy CD34+ hematopoietic stem/progenitor cells. Transcriptome studies were performed to identify gene expression changes induced by hypoxia or by overexpression of oxygen-insensitive HIF1 and HIF2 mutants. Metabolism studies were performed by 1D-NMR, and glucose consumption and lactate production levels were determined by spectrophotometric enzyme assays. CRISPR-CAS9-mediated HIF1, HIF2, and ARNT−/− lines were generated to study the functional consequences upon loss of HIF signaling, in vitro and in vivo upon transplantation of knockout lines in xenograft mice. Results Genome-wide ChIP-seq and transcriptome studies revealed that overlapping HIF1- and HIF2-controlled loci were highly enriched for various processes including metabolism, particularly glucose metabolism, but also for chromatin organization, cellular response to stress and G protein-coupled receptor signaling. ChIP-qPCR validation studies confirmed that glycolysis-related genes but not genes related to the TCA cycle or glutaminolysis were controlled by both HIF1 and HIF2 in leukemic cell lines and primary AMLs, while in healthy human CD34+ cells these loci were predominantly controlled by HIF1 and not HIF2. However, and in contrast to our initial hypotheses, CRISPR/Cas9-mediated knockout of HIF signaling did not affect growth, internal metabolite concentrations, glucose consumption or lactate production under hypoxia, not even in vivo upon transplantation of knockout cells into xenograft mice. Conclusion These data indicate that, while HIFs exert control over glycolysis but not OxPHOS gene expression in human leukemic cells, this is not critically important for their metabolic state. In contrast, inhibition of BCR-ABL did impact on glucose consumption and lactate production regardless of the presence of HIFs. These data indicate that oncogene-mediated control over glycolysis can occur independently of hypoxic signaling modules.
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- 2019
10. Enhanced expressions of FHL2 and iASPP predict poor prognosis in acute myeloid leukemia
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Hongmian Zhao, Ning Hu, Yijie Zhang, Xiaoyan Ke, Lin Fu, Depei Wu, Tong Qin, Jinlong Shi, Zhihui Zhang, Yang Jiao, Yifan Pang, Yang Chen, Yifeng Dai, Zhiheng Cheng, and Faculteit Medische Wetenschappen/UMCG
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Myeloid ,IMPACT ,medicine.medical_treatment ,Muscle Proteins ,Hematopoietic stem cell transplantation ,0302 clinical medicine ,Aged, 80 and over ,RISK ,Univariate analysis ,Hematopoietic Stem Cell Transplantation ,Intracellular Signaling Peptides and Proteins ,Myeloid leukemia ,Middle Aged ,Prognosis ,CANCER ,APOPTOSIS ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Stem cell ,Adult ,medicine.medical_specialty ,LIM-Homeodomain Proteins ,INTERACTS ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,HEMATOPOIETIC STEM-CELLS ,Molecular Biology ,Aged ,business.industry ,MUTATIONS ,medicine.disease ,Repressor Proteins ,Radiation therapy ,030104 developmental biology ,business ,Transcription Factors - Abstract
iASPP is a negative regulator of the apoptotic function of p53, and it can enhance the ability of hematopoietic stem cells to self-renew and resist chemo- and radiation therapy. Recent study showed that iASPP could impact the proliferation and apoptosis of leukemia cells by interacting with FHL2. However, whether they have prognostic significance in acute myeloid leukemia (AML) is unknown. Eighty-four AML patients with FHL2 and iASPP expression data from The Cancer Genome Atlas database were enrolled in the study. Patients with high expressions of FHL2 and iASPP had significantly shorter event-free survival (EFS) and overall survival (OS) than patients with low expressions (P = 0.005, P = 0.003, respectively). Univariate analysis indicated that high expressions of FHL2 or iASPP were unfavorable for EFS and OS (all P
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- 2019
11. Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report
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Graham P. Taylor, Steve Horwitz, Takashi Ishida, Reza Farid, Horia Bumbea, Achiléa L. Bittencourt, Ali Bazarbachi, Lee Ratner, Akifumi Takaori-Kondo, Kaoru Uchimaru, Felipe Suarez, Shigeo Fuji, Toshiki Watanabe, Alina Tanase, Yoshitaka Imaizumi, Yoshiki Tokura, Takuya Fukushima, Thomas A. Waldmann, Adrienne A. Phillips, David Sibon, Olivier Hermine, Kenji Ishitsuka, Lucy Cook, Paul Fields, Ambroise Marçais, Kunihiro Tsukasaki, Atae Utsunomiya, Matthew A. Lunning, Ilseung Choi, Juan Carlos Ramos, Masao Matsuoka, Kate Cwynarski, and Imperial College Healthcare NHS Trust- BRC Funding
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Oncology ,Cancer Research ,Skin Neoplasms ,Opportunistic infection ,COMBINATION CHEMOTHERAPY ,Disease ,Medical Oncology ,Central Nervous System Neoplasms ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,VERSUS-HOST-DISEASE ,Leukemia-Lymphoma, Adult T-Cell ,Medicine ,Human T-lymphotropic virus 1 ,0303 health sciences ,Hematopoietic Stem Cell Transplantation ,Combination chemotherapy ,3. Good health ,Treatment Outcome ,030220 oncology & carcinogenesis ,Life Sciences & Biomedicine ,NERVOUS-SYSTEM PROPHYLAXIS ,HTLV-1 PROVIRAL LOAD ,medicine.medical_specialty ,Consensus ,VIRUS TYPE-I ,Alpha interferon ,Antineoplastic Agents ,Malignancy ,Adult T-cell leukemia/lymphoma ,Special Article ,03 medical and health sciences ,Internal medicine ,LYMPHOTROPIC VIRUS ,Humans ,Transplantation, Homologous ,HEMATOPOIETIC STEM-CELLS ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,PROGNOSTIC INDEX ,030304 developmental biology ,Science & Technology ,business.industry ,CORD BLOOD TRANSPLANTATION ,medicine.disease ,Transplantation ,Clinical trial ,INTERFERON-ALPHA ,business - Abstract
Purpose Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches. Methods Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology—Human T-Lymphotropic Virus and Related Retroviruses—in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents. Results As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement). Conclusion This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL
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- 2019
12. The multifaceted role of autophagy in cancer and the microenvironment
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autophagy ,therapy ,microenvironment ,STRESS-INDUCED AUTOPHAGY ,NATURAL-KILLER-CELLS ,immune cells ,PHASE-I TRIAL ,ADVANCED SOLID TUMORS ,stroma ,cancer ,CHAPERONE-MEDIATED AUTOPHAGY ,HEMATOPOIETIC STEM-CELLS ,HYPOXIA-INDUCED AUTOPHAGY ,EFFICIENT CROSS-PRESENTATION ,OXIDATIVE MITOCHONDRIAL METABOLISM ,CHRONIC MYELOID-LEUKEMIA - Abstract
Autophagy is a crucial recycling process that is increasingly being recognized as an important factor in cancer initiation, cancer (stem) cell maintenance as well as the development of resistance to cancer therapy in both solid and hematological malignancies. Furthermore, it is being recognized that autophagy also plays a crucial and sometimes opposing role in the complex cancer microenvironment. For instance, autophagy in stromal cells such as fibroblasts contributes to tumorigenesis by generating and supplying nutrients to cancerous cells. Reversely, autophagy in immune cells appears to contribute to tumor-localized immune responses and among others regulates antigen presentation to and by immune cells. Autophagy also directly regulates T and natural killer cell activity and is required for mounting T-cell memory responses. Thus, within the tumor microenvironment autophagy has a multifaceted role that, depending on the context, may help drive tumorigenesis or may help to support anticancer immune responses. This multifaceted role should be taken into account when designing autophagy-based cancer therapeutics. In this review, we provide an overview of the diverse facets of autophagy in cancer cells and nonmalignant cells in the cancer microenvironment. Second, we will attempt to integrate and provide a unified view of how these various aspects can be therapeutically exploited for cancer therapy.
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- 2019
13. Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment
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Cristina Banella, Gianfranco Catalano, Serena Travaglini, Elvira Pelosi, Tiziana Ottone, Alessandra Zaza, Gisella Guerrera, Daniela Francesca Angelini, Pasquale Niscola, Mariadomenica Divona, Luca Battistini, Maria Screnci, Emanuele Ammatuna, Ugo Testa, Clara Nervi, Maria Teresa Voso, Nelida Ines Noguera, and Stem Cell Aging Leukemia and Lymphoma (SALL)
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Acute Myeloid Leukemia ,Cancer Research ,METFORMIN ,INHIBITION ,Seahorse XF ,ACUTE MYELOID-LEUKEMIA ,hemic and lymphatic diseases ,pharmacologic activity ,BREAST-CANCER ,HEMATOPOIETIC STEM-CELLS ,metabolism ,ascorbate ,buformin ,OXPHOS ,glycolysis ,hexokinase 1/2 ,GLUT1 ,VITAMIN-C ,TET2 FUNCTION ,CHEMOTHERAPY ,Settore MED/15 ,hexokinase 1 ,Oncology ,MUTATIONS RESULT ,ACID - Abstract
Simple Summary Acute Myeloid Leukemias (AMLs) are rapidly progressive clonal neoplastic diseases. The overall 5-year survival rate is very poor: less than 5% in older patients aged over 65 years old. Elderly AML patients are often "unfit" for intensive chemotherapy, further highlighting the need of highly effective, well-tolerated new treatment options for AMLs. Growing evidence indicates that AML blasts feature a highly diverse and flexible metabolism consistent with the aggressiveness of the disease. Based on these evidences, we targeted the metabolic peculiarity and plasticity of AML cells with an association of ascorbate, which causes oxidative stress and interferes with hexokinase activity, and buformin, which completely shuts down mitochondrial contributions in ATP production. The ascorbate-buformin combination could be an innovative therapeutic option for elderly AML patients that are resistant to therapy. In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias' (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate-buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.
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- 2022
14. The multifaceted role of autophagy in cancer and the microenvironment
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Valerie R. Wiersma, Hendrik Folkerts, Edo Vellenga, Susan Hilgendorf, and Edwin Bremer
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Carcinogenesis ,Review Article ,medicine.disease_cause ,Mice ,NATURAL-KILLER-CELLS ,PHASE-I TRIAL ,0302 clinical medicine ,Chaperone-mediated autophagy ,Neoplasms ,Drug Discovery ,Tumor Microenvironment ,HYPOXIA-INDUCED AUTOPHAGY ,HMGB1 Protein ,OXIDATIVE MITOCHONDRIAL METABOLISM ,Hypoxia ,Review Articles ,Oncogene Proteins ,0303 health sciences ,Cell Transformation, Neoplastic ,Proto-Oncogene Proteins c-bcl-2 ,ADVANCED SOLID TUMORS ,030220 oncology & carcinogenesis ,Molecular Medicine ,Beclin-1 ,Female ,CHAPERONE-MEDIATED AUTOPHAGY ,EFFICIENT CROSS-PRESENTATION ,Signal Transduction ,autophagy ,Stromal cell ,Antigen presentation ,Breast Neoplasms ,Biology ,STRESS-INDUCED AUTOPHAGY ,03 medical and health sciences ,immune cells ,stroma ,medicine ,Animals ,Humans ,cancer ,HEMATOPOIETIC STEM-CELLS ,CHRONIC MYELOID-LEUKEMIA ,030304 developmental biology ,Pharmacology ,therapy ,Tumor microenvironment ,Autophagy ,Cancer ,Fibroblasts ,medicine.disease ,microenvironment ,Mutation ,Cancer cell ,Cancer research ,Stromal Cells ,Reactive Oxygen Species - Abstract
Autophagy is a crucial recycling process that is increasingly being recognized as an important factor in cancer initiation, cancer (stem) cell maintenance as well as the development of resistance to cancer therapy in both solid and hematological malignancies. Furthermore, it is being recognized that autophagy also plays a crucial and sometimes opposing role in the complex cancer microenvironment. For instance, autophagy in stromal cells such as fibroblasts contributes to tumorigenesis by generating and supplying nutrients to cancerous cells. Reversely, autophagy in immune cells appears to contribute to tumor‐localized immune responses and among others regulates antigen presentation to and by immune cells. Autophagy also directly regulates T and natural killer cell activity and is required for mounting T‐cell memory responses. Thus, within the tumor microenvironment autophagy has a multifaceted role that, depending on the context, may help drive tumorigenesis or may help to support anticancer immune responses. This multifaceted role should be taken into account when designing autophagy‐based cancer therapeutics. In this review, we provide an overview of the diverse facets of autophagy in cancer cells and nonmalignant cells in the cancer microenvironment. Second, we will attempt to integrate and provide a unified view of how these various aspects can be therapeutically exploited for cancer therapy.
- Published
- 2018
15. Towards a Better Understanding of Cohesin Mutations in AML
- Author
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Sergi Cuartero, Andrew J. Innes, Matthias Merkenschlager, Wellcome Trust, Medical Research Council (MRC), and NIHR
- Subjects
0301 basic medicine ,Cancer Research ,Cohesin complex ,Mini Review ,cohesin ,KAPPA-B ,Biology ,lcsh:RC254-282 ,BONE-MARROW-CELLS ,03 medical and health sciences ,0302 clinical medicine ,AML ,SISTER-CHROMATID COHESION ,medicine ,HEMATOPOIETIC STEM-CELLS ,1112 Oncology and Carcinogenesis ,GENE-EXPRESSION ,Cohesin ,Inflammation ,Science & Technology ,Leukemia ,leukemia ,Myeloid leukemia ,interferon ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,MYELOID-LEUKEMIA CELLS ,Phenotype ,hematopoiesis ,Cell biology ,Chromatin ,Hematopoiesis ,REMODELING COMPLEX ,Establishment of sister chromatid cohesion ,SELF-RENEWAL ,Haematopoiesis ,030104 developmental biology ,EPIGENETIC REGULATORS ,PROGENITOR CELLS ,Oncology ,inflammation ,030220 oncology & carcinogenesis ,Interferon ,Life Sciences & Biomedicine - Abstract
Classical driver mutations in acute myeloid leukemia (AML) typically affect regulators of cell proliferation, differentiation, and survival. The selective advantage of increased proliferation, improved survival, and reduced differentiation on leukemia progression is immediately obvious. Recent large-scale sequencing efforts have uncovered numerous novel AML-associated mutations. Interestingly, a substantial fraction of the most frequently mutated genes encode general regulators of transcription and chromatin state. Understanding the selective advantage conferred by these mutations remains a major challenge. A striking example are mutations in genes of the cohesin complex, a major regulator of three-dimensional genome organization. Several landmark studies have shown that cohesin mutations perturb the balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now begin to uncover the molecular mechanisms that underpin this phenotype. Among these mechanisms is a role for cohesin in the control of inflammatory responses in HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive HSPC differentiation. Consistent with this, cohesin mutations promote resistance to inflammatory signals, and may provide a selective advantage for AML progression. In this review, we discuss recent progress in understanding cohesin mutations in AML, and speculate whether vulnerabilities associated with these mutations could be exploited therapeutically.
- Published
- 2021
16. Acute Plasmodium berghei Mouse Infection Elicits Perturbed Erythropoiesis With Features That Overlap With Anemia of Chronic Disease
- Abstract
Severe malaria anemia is one of the most common causes of morbidity and mortality arising from infection with Plasmodium falciparum. The pathogenesis of malarial anemia is complex, involving both parasite and host factors. As mouse models of malaria also develop anemia, they can provide a useful resource to study the impact of Plasmodium infections and the resulting host innate immune response on erythropoiesis. In this study, we have characterized the bone marrow and splenic responses of the erythroid as well as other hematopoietic lineages after an acute infection of Balb/c mice with Plasmodium berghei. Such characterization of the hematopoietic changes is critical to underpin future studies, using knockout mice and transgenic parasites, to tease out the interplay between host genes and parasite modulators implicated in susceptibility to malaria anemia. P. berghei infection led to a clear perturbation of steady-state erythropoiesis, with the most profound defects in polychromatic and orthochromatic erythroblasts as well as erythroid colony- and burst-forming units (CFU-E and BFU-E), resulting in an inability to compensate for anemia. The perturbation in erythropoiesis was not attributable to parasites infecting erythroblasts and affecting differentiation, nor to insufficient erythropoietin (EPO) production or impaired activation of the Signal transducer and activator of transcription 5 (STAT5) downstream of the EPO receptor, indicating EPO-signaling remained functional in anemia. Instead, the results point to acute anemia in P. berghei-infected mice arising from increased myeloid cell production in order to clear the infection, and the concomitant release of pro-inflammatory cytokines and chemokines from myeloid cells that inhibit erythroid development, in a manner that resembles the pathophysiology of anemia of chronic disease.
- Published
- 2020
17. In Vivo Pre-Instructed HSCs Robustly Execute Asymmetric Cell Divisions In Vitro
- Author
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Matthias P. Lutolf, Vincent Trachsel, Mukul Girotra, and Aline Roch
- Subjects
Cell division ,Cell ,in vivo activation ,self-renewal ,hematopoietic stem-cells ,paired daughter cells ,lcsh:Chemistry ,Mice ,Single-cell analysis ,niches ,Asymmetric cell division ,single-cell analysis ,HSC fate choice ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,Cell Differentiation ,hemic and immune systems ,General Medicine ,progenitor cells ,differentiation ,Computer Science Applications ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,Stem cell ,regulators ,Alpha interferon ,Cell fate determination ,Biology ,bone-marrow adipocytes ,Catalysis ,Article ,asymmetric cell division ,maintenance ,Inorganic Chemistry ,c-myc ,medicine ,Animals ,Cell Lineage ,quiescence ,Physical and Theoretical Chemistry ,Molecular Biology ,Gene Expression Profiling ,Organic Chemistry ,Interferon-alpha ,hematopoietic stem cells ,Mice, Inbred C57BL ,Gene Expression Regulation ,lcsh:Biology (General) ,lcsh:QD1-999 ,metabolism - Abstract
Hematopoietic stem cells (HSCs) are responsible for life-long production of all mature blood cells. Under homeostasis, HSCs in their native bone marrow niches are believed to undergo asymmetric cell divisions (ACDs), with one daughter cell maintaining HSC identity and the other committing to differentiate into various mature blood cell types. Due to the lack of key niche signals, in vitro HSCs differentiate rapidly, making it challenging to capture and study ACD. To overcome this bottleneck, in this study, we used interferon alpha (IFN&alpha, ) treatment to &rdquo, pre-instruct&rdquo, HSC fate directly in their native niche, and then systematically studied the fate of dividing HSCs in vitro at the single cell level via time-lapse analysis, as well as multigene and protein expression analysis. Triggering HSCs&rsquo, exit from dormancy via IFN&alpha, was found to significantly increase the frequency of asynchronous divisions in paired daughter cells (PDCs). Using single-cell gene expression analyses, we identified 12 asymmetrically expressed genes in PDCs. Subsequent immunocytochemistry analysis showed that at least three of the candidates, i.e., Glut1, JAM3 and HK2, were asymmetrically distributed in PDCs. Functional validation of these observations by colony formation assays highlighted the implication of asymmetric distribution of these markers as hallmarks of HSCs, for example, to reliably discriminate committed and self-renewing daughter cells in dividing HSCs. Our data provided evidence for the importance of in vivo instructions in guiding HSC fate, especially ACD, and shed light on putative molecular players involved in this process. Understanding the mechanisms of cell fate decision making should enable the development of improved HSC expansion protocols for therapeutic applications.
- Published
- 2020
18. Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche
- Author
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Boshi Wang, Uilke Brouwer, Marco Demaria, Thijmen van Vliet, Xiaohong Peng, Robert P. Coppes, Yi Wu, Lara Barazzuol, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Molecular Neuroscience and Ageing Research (MOLAR), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
Senescence ,Cancer Research ,Cell cycle checkpoint ,CLEARANCE ,Immunology ,SALIVARY-GLANDS ,BCL-2 ,Inflammation ,Biology ,Xerostomia ,Article ,Salivary Glands ,Cellular and Molecular Neuroscience ,Mice ,NECK-CANCER ,medicine ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,Progenitor cell ,lcsh:QH573-671 ,Stem Cell Niche ,Senolytic ,Cellular Senescence ,Cell Proliferation ,DAMAGE ,Adult stem cells ,Sulfonamides ,Aniline Compounds ,Secretory Pathway ,Salivary gland ,Radiotherapy ,lcsh:Cytology ,Stem Cells ,Cell Biology ,Up-Regulation ,Tissue Degeneration ,Mice, Inbred C57BL ,Radiation Injuries, Experimental ,medicine.anatomical_structure ,Cancer research ,EX-VIVO EXPANSION ,Female ,IONIZING-RADIATION ,OVEREXPRESSION ,medicine.symptom ,Stem cell - Abstract
Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.
- Published
- 2020
19. Innovations, challenges, and minimal information for standardization of humanized mice
- Subjects
HEPATITIS-B ,regenerative medicine ,BREAST-CANCER CELLS ,MOUSE MODEL ,VIRUS-INFECTION ,humanized mice ,HUMAN HEPATOCYTES ,XENOGRAFTS ,HEMATOPOIETIC STEM-CELLS ,IMMUNE-SYSTEM ,infections ,immuno-oncology ,LIVER CHIMERIC MICE ,PDX ,ANTIBODY THERAPY - Abstract
Mice xenotransplanted with human cells and/or expressing human gene products (also known as "humanized mice") recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevantin vivocontext for understanding of human-specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring different facets of humanized mouse models has steadily increased in past years, it is becoming evident that standardized reporting is needed in the field. Therefore, an international community-driven resource called "Minimal Information for Standardization of Humanized Mice" (MISHUM) has been created for the purpose of enhancing rigor and reproducibility of studies in the field. WithinMISHUM, we propose comprehensive guidelines for reporting critical information generated using humanized mice.
- Published
- 2020
20. Innovations, challenges, and minimal information for standardization of humanized mice
- Author
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Michael A. Brehm, Carol J. Bult, Johannes Sam, Florian Klein, Silvia Guionaud, Karl-Dimiter Bissig, James P. Di Santo, Anja Kathrin Wege, Terrence Meeham, Dominique Bonnet, Scott G. Kitchen, Livio Trusolino, Kourosh Saeb-Parsy, Christian Münz, Brian Soper, Kristina E. Howard, Amar Deep Sharma, Renata Stripecke, Estefanía Rodríguez, Leonard D. Shultz, Li-Chin Yao, Andreas Trumpp, Jan Jacob Schuringa, University of Zurich, Stripecke, Renata, Stripecke, Renata [0000-0001-7756-8460], Münz, Christian [0000-0001-6419-1940], Schuringa, Jan Jacob [0000-0001-8452-8555], Trumpp, Andreas [0000-0002-6212-3466], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Medicine (General) ,Standardization ,HEPATITIS-B ,Review ,Mice, SCID ,QH426-470 ,10263 Institute of Experimental Immunology ,Regenerative medicine ,Chromatin, Epigenetics, Genomics & Functional Genomics ,immuno‐oncology ,Mice ,0302 clinical medicine ,Neoplasms ,Medicine ,infections ,LIVER CHIMERIC MICE ,BREAST-CANCER CELLS ,MOUSE MODEL ,humanized mice ,Molecular Medicine ,Heterografts ,Immunology ,regenerative medicine ,Context (language use) ,610 Medicine & health ,Guidelines as Topic ,VIRUS-INFECTION ,Computational biology ,03 medical and health sciences ,R5-920 ,Genetics ,XENOGRAFTS ,immuno-oncology ,PDX ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,business.industry ,Reproducibility of Results ,Disease Models, Animal ,HUMAN HEPATOCYTES ,030104 developmental biology ,1313 Molecular Medicine ,Humanized mouse ,570 Life sciences ,biology ,IMMUNE-SYSTEM ,Breast cancer cells ,Antibody therapy ,business ,030217 neurology & neurosurgery ,ANTIBODY THERAPY - Abstract
Mice xenotransplanted with human cells and/or expressing human gene products (also known as “humanized mice”) recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo context for understanding of human‐specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring different facets of humanized mouse models has steadily increased in past years, it is becoming evident that standardized reporting is needed in the field. Therefore, an international community‐driven resource called “Minimal Information for Standardization of Humanized Mice” (MISHUM) has been created for the purpose of enhancing rigor and reproducibility of studies in the field. Within MISHUM, we propose comprehensive guidelines for reporting critical information generated using humanized mice., Humanized mice are at the forefront of biomedical research and becoming more mainstream preclinical models. This comprehensive review talks about innovations and challenges regarding the reconstitution of human immunity and introduces “Minimal Information for Standardization of Humanized Mice” (MISHUM).
- Published
- 2020
21. The human fetal thymus generates invariant effector γδ T cells
- Author
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Ling Ma, Bart Vandekerckhove, Naomi McGovern, Paola Tieppo, Karin Weening, Deborah Gatti, Maria Papadopoulou, David Vermijlen, Glenn Goetgeluk, Alexandra Cogan, Françoise Gosselin, Florent Ginhoux, Jerry Kok Yen Chan, Nicolas Dauby, and Catherine Donner
- Subjects
Male ,EXPRESSION ,SELECTION ,TRANSCRIPTION FACTOR PLZF ,T cell ,Immunology ,Thymus Gland ,Article ,Fetus ,Antigen ,DNA Nucleotidylexotransferase ,Precursor cell ,Immunologie ,medicine ,Medicine and Health Sciences ,Humans ,Immunology and Allergy ,HEMATOPOIETIC STEM-CELLS ,Progenitor cell ,MACROPHAGES ,Child ,Research Articles ,Cells, Cultured ,Thymocytes ,biology ,PROGENITORS ,Effector ,Infant ,RNA-Binding Proteins ,Receptors, Antigen, T-Cell, gamma-delta ,THYMOCYTES ,Sciences bio-médicales et agricoles ,Cell biology ,Haematopoiesis ,MICE ,medicine.anatomical_structure ,DIFFERENTIATION ,Granzyme ,Terminal deoxynucleotidyl transferase ,MONOCYTES ,Child, Preschool ,embryonic structures ,biology.protein ,Female - Abstract
Tieppo et al. show that the human fetal thymus generates invariant γδ T cells with programmed effector functions. This is due to an intrinsic property of fetal HSPCs caused by high expression of the RNA-binding protein Lin28b., In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant γδ T cells occur in humans is not known. Here we found that, unlike postnatal γδ thymocytes, human fetal γδ thymocytes were functionally programmed (e.g., IFNγ, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions., Graphical Abstract
- Published
- 2019
22. Interferon priming is essential for human CD34+ cell-derived plasmacytoid dendritic cell maturation and function
- Author
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Matt Porteus, Niels Uldbjerg, Nadia R. Roan, L Kjær, Satish K. Pillai, Anders Laustsen, J H Egedahl, Paul W. Denton, Christian Krapp, Hai Q Tang, Martin R. Jakobsen, Rasmus O. Bak, Charlotte Christie Petersen, and Mette Nyegaard
- Subjects
0301 basic medicine ,ADJUVANT ACTIVITY ,General Physics and Astronomy ,Priming (immunology) ,Antigens, CD34 ,Receptor, Interferon alpha-beta ,Plasmacytoid dendritic cell ,Polymerase Chain Reaction ,0302 clinical medicine ,MAMMALIAN-CELLS ,Interferon ,Receptors, Immunologic ,lcsh:Science ,Cells, Cultured ,Gene Editing ,Multidisciplinary ,Cell Differentiation ,hemic and immune systems ,Nucleotidyltransferases ,Cell biology ,I-INTERFERON ,Haematopoiesis ,030220 oncology & carcinogenesis ,SYNTHETIC SIRNA ,Interferon Type I ,DEAD Box Protein 58 ,medicine.drug ,BONE-MARROW ,FLT3 LIGAND ,Science ,Enzyme-Linked Immunosorbent Assay ,macromolecular substances ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,medicine ,Humans ,HEMATOPOIETIC STEM-CELLS ,Progenitor cell ,Interleukin-6 ,IFN-ALPHA ,TLR9 ,DIABETES-MELLITUS ,Dendritic Cells ,General Chemistry ,TLR7 ,030104 developmental biology ,PROGENITOR CELLS ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,lcsh:Q ,CRISPR-Cas Systems - Abstract
Plasmacytoid dendritic cells (pDC) are essential for immune competence. Here we show that pDC precursor differentiated from human CD34+ hematopoietic stem and progenitor cells (HSPC) has low surface expression of pDC markers, and has limited induction of type I interferon (IFN) and IL-6 upon TLR7 and TLR9 agonists treatment; by contrast, cGAS or RIG-I agonists-mediated activation is not altered. Importantly, after priming with type I and II IFN, these precursor pDCs attain a phenotype and functional activity similar to that of peripheral blood-derived pDCs. Data from CRISPR/Cas9-mediated genome editing of HSPCs further show that HSPC-pDCs with genetic modifications can be obtained, and that expression of the IFN-α receptor is essential for the optimal function, but dispensable for the differentiation, of HSPC-pDC percursor. Our results thus demonstrate the biological effects of IFNs for regulating pDC function, and provide the means of generating of gene-modified human pDCs., Plasmacytoid dendritic cells (pDC) are an important regulator of immune responses. Here the authors show that pDC precursors, similar to peripheral blood-derived pDCs, can be differentiated from human CD34+ hematopoietic stem and progenitor cells, with type I/II IFN priming being required for their functional maturation and differentiation.
- Published
- 2018
23. Increased Expression of RUNX1 in Liver Correlates with NASH Activity Score in Patients with Non-Alcoholic Steatohepatitis (NASH)
- Author
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Thomas S. Weiss, R Dayoub, Savneet Kaur, Maria Thomas, Reinhard Guthke, Shvetank Sharma, Mohsin Hassan, Dinesh M. Tripathi, Sukriti Baweja, Hamda Siddiqui, Chaggan Bihari, Shiv Kumar Sarin, Sumati Rohilla, Preety Rawal, and Sebastian Vlaic
- Subjects
0301 basic medicine ,RUNX1 ,Carcinoma, Hepatocellular ,Angiogenesis ,610 Medizin ,Palmitic Acid ,Inflammation ,Biology ,In Vitro Techniques ,Article ,03 medical and health sciences ,angiogenesis ,Mice ,0302 clinical medicine ,Fibrosis ,hemic and lymphatic diseases ,Gene expression ,medicine ,steatosis ,Human Umbilical Vein Endothelial Cells ,Gene silencing ,Animals ,Humans ,lcsh:QH301-705.5 ,Cells, Cultured ,fatty liver ,ddc:610 ,Cell adhesion molecule ,Fatty liver ,Liver Neoplasms ,non-alcoholic fatty liver disease ,Endothelial Cells ,HEMATOPOIETIC STEM-CELLS ,KINASE C-EPSILON ,GROWTH-FACTOR ,INSULIN-RESISTANCE ,ANGIOGENESIS ,TRANSCRIPTION ,MACROPHAGES ,MECHANISM ,FIBROSIS ,GENES ,inflammation ,General Medicine ,medicine.disease ,Flow Cytometry ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,Liver ,030220 oncology & carcinogenesis ,embryonic structures ,Core Binding Factor Alpha 2 Subunit ,Cancer research ,medicine.symptom ,Steatohepatitis - Abstract
Given the important role of angiogenesis in liver pathology, the current study investigated the role of Runt-related transcription factor 1 (RUNX1), a regulator of developmental angiogenesis, in the pathogenesis of non-alcoholic steatohepatitis (NASH). Quantitative RT-PCRs and a transcription factor analysis of angiogenesis-associated differentially expressed genes in liver tissues of healthy controls, patients with steatosis and NASH, indicated a potential role of RUNX1 in NASH. The gene expression of RUNX1 was correlated with histopathological attributes of patients. The protein expression of RUNX1 in liver was studied by immunohistochemistry. To explore the underlying mechanisms, in vitro studies using RUNX1 siRNA and overexpression plasmids were performed in endothelial cells (ECs). RUNX1 expression was significantly correlated with inflammation, fibrosis and NASH activity score in NASH patients. Its expression was conspicuous in liver non-parenchymal cells. In vitro, factors from steatotic hepatocytes and/or VEGF or TGF-β significantly induced the expression of RUNX1 in ECs. RUNX1 regulated the expression of angiogenic and adhesion molecules in ECs, including CCL2, PECAM1 and VCAM1, which was shown by silencing or over-expression of RUNX1. Furthermore, RUNX1 increased the angiogenic activity of ECs. This study reports that steatosis-induced RUNX1 augmented the expression of adhesion and angiogenic molecules and properties in ECs and may be involved in enhancing inflammation and disease severity in NASH.
- Published
- 2019
24. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC
- Subjects
EXPERIMENTAL AUTOIMMUNE MYOCARDITIS ,TOLL-LIKE RECEPTORS ,Ischaemic cardiomyopathy ,Peripartum cardiomyopathy ,ATRIAL-NATRIURETIC-PEPTIDE ,EXPERIMENTAL DIABETIC CARDIOMYOPATHY ,Macrophage ,Viral cardiomyopathy ,Diabetic cardiomyopathy ,ISCHEMIC-HEART-DISEASE ,Autoimmune cardiomyopathy ,Toxic cardiomyopathy ,GIANT-CELL MYOCARDITIS ,Immune system ,T-cell ,Genetic cardiomyopathy ,HEMATOPOIETIC STEM-CELLS ,CARDIAC TROPONIN-I ,Hypertensive cardiomyopathy ,TUMOR-NECROSIS-FACTOR - Abstract
Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.
- Published
- 2018
25. Visualizing the Selectivity and Dynamics of Interferon Signaling In Vivo
- Published
- 2019
26. Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding
- Author
-
Leonid Bystrykh, Eveline S. J. M. de Bont, Bertien Ausema, Mirjam E. Belderbos, Sabrina Jacobs, Sharlaine Sowdagar, Erik Zwart, Taco Koster, Gerald de Haan, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Male ,0301 basic medicine ,DYNAMICS ,BLOOD ,medicine.medical_treatment ,Mice, SCID ,Biochemistry ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,HETEROGENEITY ,Child ,Mice, Knockout ,Genetics ,Hematology ,Leukemia ,medicine.anatomical_structure ,Child, Preschool ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Clone (B-cell biology) ,medicine.medical_specialty ,Adolescent ,Xenotransplantation ,BONE-MARROW ,Immunology ,SUBCLONES ,ACUTE MYELOID-LEUKEMIA ,Biology ,03 medical and health sciences ,Cancer stem cell ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Internal medicine ,medicine ,Animals ,Humans ,BREAST-CANCER ,HEMATOPOIETIC STEM-CELLS ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,Genetic heterogeneity ,Models, Immunological ,Cell Biology ,medicine.disease ,EVOLUTION ,030104 developmental biology ,Bone marrow ,Neoplasm Transplantation ,Clonal selection - Abstract
Genetic and phenotypic heterogeneity of human leukemia is thought to drive leukemia progression through a Darwinian process of selection and evolution of increasingly malignant clones. However, the lack of markers that uniquely identify individual leukemia clones precludes high-resolution tracing of their clonal dynamics. Here, we use cellular barcoding to analyze the clonal behavior of patient-derived leukemia-propagating cells (LPCs) in murine xenografts. Using a leukemic cell line and diagnostic bone marrow cells from 6 patients with B-progenitor cell acute lymphoblastic leukemia, we demonstrate that patient-derived xenografts were highly polyclonal, consisting of tens to hundreds of LPC clones. The number of clones was stable within xenografts but strongly reduced upon serial transplantation. In contrast to primary recipients, in which clonal composition was highly diverse, clonal composition in serial xenografts was highly similar between recipients of the same donor and reflected donor clonality, supporting a deterministic, clone-size-based model for clonal selection. Quantitative analysis of clonal abundance in several anatomic sites identified 2 types of anatomic asymmetry. First, clones were asymmetrically distributed between different bones. Second, clonal composition in the skeleton significantly differed from extramedullary sites, showing similar numbers but different clone sizes. Altogether, this study shows that cellular barcoding and xenotransplantation providea useful model to study the behavior of patient-derived LPC clones, which provides insights relevant for experimental studies on cancer stem cells and for clinical protocols for the diagnosis and treatment of leukemia.
- Published
- 2017
27. Interrogating open issues in cancer precision medicine with patient-derived xenografts
- Subjects
METASTATIC COLORECTAL-CANCER ,LUNG-CANCER ,NEGATIVE BREAST CANCERS ,HEMATOPOIETIC STEM-CELLS ,MOUSE MODEL ,DUCTAL PANCREATIC-CANCER ,CIRCULATING TUMOR-CELLS ,IN-VIVO ,ACQUIRED-RESISTANCE ,GENE-EXPRESSION - Abstract
Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective ofEurOPDX, an international initiative devoted to PDX-based research.
- Published
- 2017
28. The power of fat and its adipose-derived stromal cells
- Subjects
GRAFT-SURVIVAL ,adipose-derived stromal/stem cells ,lipofilling ,scar treatment ,BREAST ,stromal vascular fraction ,dermal scar ,adipose tissue ,HYPERTROPHIC SCAR ,POSTMASTECTOMY PAIN SYNDROME ,CLEFT-LIP REPAIR ,TISSUE ,EXPERIENCE ,HEMATOPOIETIC STEM-CELLS ,REGENERATIVE CELLS ,RADIOTHERAPY - Abstract
Lipofilling or lipografting is a novel and promising treatment method for reduction or prevention of dermal scars after injury. Ample anecdotal evidence from case reports supports the scar-reducing properties of adipose tissue grafts. However, only a few properly controlled and designed clinical trials have been conducted thus far on this topic. Also, the underlying mechanism by which lipofilling improves scar aspect and reduces neuropathic scar pain remains largely undiscovered. Adipose-derived stromal or stem cells (ADSC) are often described to be responsible for this therapeutic effect of lipofilling. We review the recent literature and discuss anticipated mechanisms that govern anti-scarring capacity of adipose tissue and its ADSC. Both clinical and animal studies clearly demonstrated that lipofilling and ADSC influence processes associated with wound healing, including extracellular matrix remodelling, angiogenesis and modulation of inflammation in dermal scars. However, randomized clinical trials, providing sufficient level of evidence for lipofilling and/or ADSC as an anti-scarring treatment, are lacking yet warranted in the near future. (c) 2017 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd
- Published
- 2017
29. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation
- Author
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Yan, K.Z., Rousseau, J., Littlejohn, R.O., Kiss, C., Lehman, A., Rosenfeld, J.A., Stumpel, C.T.R., Stegmann, A.P.A., Robak, L., Scaglia, F., Nguyen, T.T.M., Fu, H., Ajeawung, N.F., Camurri, M.V., Li, L., Gardham, A., Panis, B., Almannai, M., Sacoto, M.J.G., Baskin, B., Ruivenkamp, C., Xia, F., Bi, W., Cho, M.T., Potjer, T.P., Santen, G.W.E., Parker, M.J., Canham, N., McKinnon, M., Potocki, L., MacKenzie, J.J., Roeder, E.R., Campeau, P.M., Yang, X.J., DDD Study, CAUSES Study, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA KG Lab Centraal Lab (9)
- Subjects
0301 basic medicine ,Male ,Developmental Disabilities ,PZP DOMAIN ,HBO1 ACETYLTRANSFERASE ,Histones ,Mice ,Intellectual disability ,Global developmental delay ,Child ,Genetics (clinical) ,Histone Acetyltransferases ,Genetics ,Mice, Knockout ,ZINC-FINGER PROTEIN ,Nuclear Proteins ,Acetylation ,Syndrome ,Chromatin ,DNA-Binding Proteins ,Histone ,Muscle Hypotonia ,Female ,EXPRESSION ,Adolescent ,Biology ,KAT6B ,Article ,03 medical and health sciences ,Histone H3 ,Intellectual Disability ,medicine ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,Epigenetics ,Histone H3 acetylation ,Alleles ,Adaptor Proteins, Signal Transducing ,CAUSE GENITOPATELLAR SYNDROME ,Lysine ,PHD FINGER ,medicine.disease ,Bromodomain ,Mice, Inbred C57BL ,030104 developmental biology ,DE-NOVO MUTATIONS ,Face ,Mutation ,biology.protein ,Carrier Proteins ,CAENORHABDITIS-ELEGANS - Abstract
Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Syrhptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
- Published
- 2017
30. Acute myeloid leukemia in the vascular niche
- Subjects
OVEREXPRESSING ANGIOPOIETIN-1 ,Leukemia ,BONE-MARROW ,ANTITUMOR-ACTIVITY ,Vascular targeting agents ,EXPERIMENTAL-TUMORS ,TARGETING AGENT ,SELF-RENEWAL ,Clinical trials ,Vasculogenesis ,ENDOTHELIAL GROWTH-FACTOR ,Bone marrow ,HEMATOPOIETIC STEM-CELLS ,Angiogenesis ,RESISTANCE CAM-DR ,COMBRETASTATIN A-4 PHOSPHATE - Abstract
The greatest challenge in treating acute myeloid leukemia (AML) is refractory disease. With approximately 60-80% of AML patients dying of relapsed disease, there is an urgent need to define and target mechanisms of drug resistance. Unfortunately, targeting cell-intrinsic resistance has failed to improve clinical outcomes in AML Emerging data show that cell-extrinsic factors in the bone marrow microenvironment protect and support AML cells. The vascular niche, in particular, regulates AML cell survival and cell cycling by both paracrine secretion and adhesive contact with endothelial cells. Moreover, AML cells can functionally integrate within vascular endothelia, undergo quiescence, and resist cytotoxic chemotherapy. Together, these findings support the notion of blood vessels as sanctuary sites for AML Therefore, vascular targeting agents may serve to remit AML. Several early phase clinical trials have tested anti-angiogenic agents, leukemia mobilizing agents, and vascular disrupting agents in AML patients. In general, these agents can be safely administered to AML patients and cardiovascular side effects were reported. Response rates to vascular targeting agents in AML have been modest; however, a majority of vascular targeting trials in AML are monotherapy in design and indiscriminate in patient recruitment. When considering the chemosensitizing effects of targeting the microenvironment, there is a strong rationale to build upon these early phase clinical trials and initiate phase IB/II trials of combination therapy where vascular targeting agents are positioned as priming agents for cytotoxic chemotherapy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
- Published
- 2016
31. The role of hydrogen sulfide in aging and age-related pathologies
- Subjects
gasotransmitters ,VEIN ENDOTHELIAL-CELLS ,H2S ,CYSTATHIONINE BETA-SYNTHASE ,aging ,hallmarks of aging ,ACTIVATED PROTEIN-KINASE ,NF-KAPPA-B ,hydrogen sulfide ,DEPRIVATION-INDUCED APOPTOSIS ,DNA-DAMAGE-RESPONSE ,ONCOGENE-INDUCED SENESCENCE ,HEMATOPOIETIC STEM-CELLS ,LIFE-SPAN EXTENSION ,OXIDATIVE STRESS - Abstract
When humans grow older, they experience inevitable and progressive loss of physiological function, ultimately leading to death. Research on aging largely focuses on the identification of mechanisms involved in the aging process. Several proposed aging theories were recently combined as the 'hallmarks of aging'. These hallmarks describe (patho-) physiological processes that together, when disrupted, determine the aging phenotype. Sustaining evidence shows a potential role for hydrogen sulfide (H2S) in the regulation of aging.Nowadays, H2S is acknowledged as an endogenously produced signaling molecule with various (patho-) physiological effects. H2S is involved in several diseases including pathologies related to aging. In this review, the known, assumed and hypothetical effects of hydrogen sulfide on the aging process will be discussed by reviewing its actions on the hallmarks of aging and on several age-related pathologies.
- Published
- 2016
32. Bone Marrow Transplantation 1957-2019
- Author
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Francesco Dazzi, Elizabeth Simpson, Leukaemia & Lymphoma Research 'Beating Blood Cancers', Cancer Research UK, and Medical Research Council (MRC)
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,medicine.medical_specialty ,Bone marrow transplantation ,medicine.medical_treatment ,Graft versus tumour ,Immunology ,graft-vs.-tumour ,Review ,History, 21st Century ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Y-ANTIGEN ,medicine ,Humans ,Immunology and Allergy ,histocompatibility ,HEMATOPOIETIC STEM-CELLS ,Intensive care medicine ,Bone Marrow Transplantation ,Science & Technology ,immunosuppression ,business.industry ,INFUSION ,Immunosuppression ,History, 20th Century ,Histocompatibility ,Transplantation ,graft-vs.-host ,030104 developmental biology ,T-CELLS ,lcsh:RC581-607 ,business ,Life Sciences & Biomedicine ,030215 immunology ,transplantation - Abstract
Clinical bone marrow transplantation started in 1957 at a time when remarkably little was known about hematopoietic stems cells, immune responses to transplants or the identity of transplant antigens. This review will delineate the substantial increase in knowledge about these three areas gained between then and 1992 when the Ceppellini School course on Bone Marrow Transplantation was held, along with the progress made in clinical application, as well as the stumbling blocks that remained to be overcome by further research to advance knowledge. It will outline the significant progress made between 1992 and the present year, 2019, and the remaining problems.
- Published
- 2019
33. The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF
- Author
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Farzaneh Fayazpour, Louis Boon, Manon Vanheerswynghels, Kim Deswarte, Arne Martens, Simon Tavernier, Jessica Vetters, Nozomi Takahashi, Justine Van Moorleghem, Sophie Janssens, Geert van Loo, Sigrid Wahlen, Sofie De Prijck, Peter Vandenabeele, Karl Vergote, Eric Vivier, Bart N. Lambrecht, Mary J. van Helden, Unit of Immunoregulation and Mucosal Immunology [Ghent, Belgium], VIB Inflammation Research Center [Ghent, Belgium], Université de Strasbourg (UNISTRA), Groupe d'études orientales, slaves et néo-helléniques (GEO), Universiteit Gent = Ghent University (UGENT), Bioceros BV, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Department of Respiratory Medicine, Imperial College London, ER Stress and Inflammation [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Erasmus MC other, Pulmonary Medicine, Universiteit Gent = Ghent University [Belgium] (UGENT), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,PROTECTS CELLS ,Programmed cell death ,Cell Survival ,Immunology ,Cell ,B-CELL ,Regulator ,BCL-2 ,MATURATION ,Mice ,03 medical and health sciences ,NATURAL-KILLER-CELLS ,0302 clinical medicine ,Ubiquitin ,immune system diseases ,Lymphopenia ,hemic and lymphatic diseases ,medicine ,Medicine and Health Sciences ,KINASE ,Animals ,Homeostasis ,Immunology and Allergy ,HEMATOPOIETIC STEM-CELLS ,Research Articles ,Tumor Necrosis Factor alpha-Induced Protein 3 ,PI3K/AKT/mTOR pathway ,biology ,Tumor Necrosis Factor-alpha ,Chemistry ,TOR Serine-Threonine Kinases ,Brief Definitive Report ,Biology and Life Sciences ,Phenotype ,3. Good health ,Cell biology ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,T-CELLS ,SURVIVAL ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Tumor necrosis factor alpha ,OVEREXPRESSION ,030215 immunology - Abstract
The study of Vetters et al. identifies the ubiquitin-modifying enzyme A20 as a critical regulator of mTOR. Loss of A20 unleashes mTOR activity and induces NK cell death, underscoring the need for a tightly controlled mTOR pathway for proper NK cell homeostasis., The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.
- Published
- 2019
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- View/download PDF
34. CXCR4, but not CXCR3, drives CD8(+) T-cell entry into and migration through the murine bone marrow
- Author
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Graham Anderson, Mark Hoogenboezem, Edith Slot, Martijn A. Nolte, Marieke Goedhart, Stephanie Gessel, Carlijn Voermans, Jaap D. van Buul, Ellis Gielen, Sulima Geerman, Beth Lucas, Stephan Huveneers, Robbert van der Voort, Timo Rademakers, Harry Dolstra, Graduate School, AII - Inflammatory diseases, Landsteiner Laboratory, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, Clinical Haematology, and CCA - Cancer biology and immunology
- Subjects
0301 basic medicine ,EXPRESSION ,Stromal cell ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Immunology ,T cells ,EFFECTOR ,CHEMOKINE RECEPTOR CXCR3 ,Biology ,CXCR3 ,LYMPHOCYTES ,CXCR4 ,03 medical and health sciences ,Chemokine receptor ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Bone marrow ,HEMATOPOIETIC STEM-CELLS ,Migration ,IN-VIVO ,stromal cells ,MEMORY ,PROLIFERATION ,CXCL12 ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,MAINTENANCE ,SURVIVAL ,CD8 ,030215 immunology ,Homing (hematopoietic) - Abstract
The BM serves as a blood-forming organ, but also supports the maintenance and immune surveillance function of many T cells. Yet, in contrast to other organs, little is known about the molecular mechanisms that drive T-cell migration to and localization inside the BM. As BM accumulates many CXCR3-expressing memory CD8+ T cells, we tested the involvement of this chemokine receptor, but found that CXCR3 is not required for BM entry. In contrast, we could demonstrate that CXCR4, which is highly expressed on both naive and memory CD8+ T cells in BM, is critically important for homing of all CD8+ T-cell subsets to the BM in mice. Upon entry into the BM parenchyma, both naïve and memory CD8+ T cells locate close to sinusoidal vessels. Intravital imaging experiments revealed that CD8 T cells are surprisingly immobile and we found that they interact with ICAM-1+VCAM-1+BP-1+ perivascular stromal cells. These cells are the major source of CXCL12, but also express key survival factors and maintenance cytokines IL-7 and IL-15. We therefore conclude that CXCR4 is not only crucial for entry of CD8+ T cells into the BM, but also controls their subsequent localization toward BM niches that support their survival.
- Published
- 2019
35. Neutrophils instruct homeostatic and pathological states in naive tissues
- Author
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Maria Casanova-Acebes, Magdalena Leiva, Juan A. Quintana, José Ángel Nicolás-Ávila, Sapna Devi, Héctor Peinado, José M. Adrover, Andrés Hidalgo, Georgiana Crainiciuc, Noelia A-Gonzalez, Lai Guan Ng, Susana García-Silva, Arthur Mortha, Jackson LiangYao Li, Matthias Gunzer, Miriam Merad, Oliver Soehnlein, Takashi Nagasawa, Kyle Burrows, Akhila Balachander, Iván Ballesteros, Christian Weber, Linnea A. Weiss, Andrea Rubio-Ponce, Deutsche Forschungsgemeinschaft (Alemania), Ministerio de Ciencia, Innovación y Universidades (España), Comunidad de Madrid (España), Canadian Institutes of Health Research, Fundación ProCNIC, Biochemie, and RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis
- Subjects
Male ,0301 basic medicine ,Lung Neoplasms ,Transcription, Genetic ,P-selectin ,Neutrophils ,Phagocytosis ,ROR-GAMMA-T ,BONE-MARROW ,Immunology ,Medizin ,Biology ,GRANULOCYTES ,medicine.disease_cause ,Interleukin-23 ,Article ,PHAGOCYTOSIS ,Mice ,03 medical and health sciences ,RAR-related orphan receptor gamma ,FLUORESCENT PROTEIN ,Granulocyte Colony-Stimulating Factor ,medicine ,Animals ,Immunology and Allergy ,Neoplasm Invasiveness ,HEMATOPOIETIC STEM-CELLS ,HETEROGENEITY ,MACROPHAGES ,Lung ,Melanoma ,Research Articles ,Mice, Knockout ,P-SELECTIN ,medicine.disease ,3. Good health ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,MAINTENANCE ,Neutrophil Infiltration ,Female ,Bone marrow ,Carcinogenesis ,Infiltration (medical) ,Homeostasis - Abstract
Neutrophils enter tissues to mediate immunity and inflammation. Casanova-Acebes et al. show that migration into naive tissues is equally important. In the intestine, they provide remote support to hematopoietic niches, whereas in the lungs they regulate circadian transcription and metastasis., Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states., Graphical Abstract
- Published
- 2018
36. The role of hydrogen sulfide in aging and age-related pathologies
- Author
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Henri G. D. Leuvenink, Bernard W. Perridon, Jan-Luuk Hillebrands, Harry van Goor, Eelke M. Bos, and Neurosurgery
- Subjects
0301 basic medicine ,gasotransmitters ,Aging ,CYSTATHIONINE BETA-SYNTHASE ,NF-KAPPA-B ,hallmarks of aging ,hydrogen sulfide ,Review ,Biology ,DEPRIVATION-INDUCED APOPTOSIS ,Genomic Instability ,Epigenesis, Genetic ,03 medical and health sciences ,Age related ,ONCOGENE-INDUCED SENESCENCE ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,LIFE-SPAN EXTENSION ,OXIDATIVE STRESS ,Physiological function ,VEIN ENDOTHELIAL-CELLS ,H2S ,ACTIVATED PROTEIN-KINASE ,Cell Biology ,030104 developmental biology ,Biochemistry ,DNA-DAMAGE-RESPONSE ,Oncogene-induced senescence ,Neuroscience ,Signal Transduction - Abstract
When humans grow older, they experience inevitable and progressive loss of physiological function, ultimately leading to death. Research on aging largely focuses on the identification of mechanisms involved in the aging process. Several proposed aging theories were recently combined as the 'hallmarks of aging'. These hallmarks describe (patho-) physiological processes that together, when disrupted, determine the aging phenotype. Sustaining evidence shows a potential role for hydrogen sulfide (H2S) in the regulation of aging. Nowadays, H2S is acknowledged as an endogenously produced signaling molecule with various (patho-) physiological effects. H2S is involved in several diseases including pathologies related to aging. In this review, the known, assumed and hypothetical effects of hydrogen sulfide on the aging process will be discussed by reviewing its actions on the hallmarks of aging and on several age-related pathologies.
- Published
- 2016
37. Origin, fate and dynamics of macrophages at central nervous system interfaces
- Author
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Josef Priller, Steffen Jung, Slava Epelman, Nora Hagemeyer, Sten Linnarsson, Marta Joana Costa Jordão, Fabio M.V. Rossi, Martin Kerschensteiner, Katrin Kierdorf, Fabiola Prutek, Frederic Geissmann, Lukas Amann, Tobias Goldmann, Robert Zeiser, Martin Krueger, Giuseppe Locatelli, Ori Staszewski, Peter Wieghofer, Ingo Bechmann, Marco Prinz, Hannah Hochgerner, and Kathrin Frenzel
- Subjects
Central Nervous System ,0301 basic medicine ,genetics [Trans-Activators] ,Cellular differentiation ,Monocytes ,Mice ,Immunology and Allergy ,metabolism [Trans-Activators] ,MYELOID CELLS ,physiology [Hematopoietic Stem Cells] ,IN-VIVO ,Cells, Cultured ,Mice, Knockout ,MOUSE-BRAIN ,CARDIAC MACROPHAGES ,Microglia ,Cell Differentiation ,Cell biology ,ALZHEIMERS-DISEASE ,medicine.anatomical_structure ,1107 Immunology ,TISSUE MACROPHAGES ,Choroid plexus ,Life Sciences & Biomedicine ,proto-oncogene protein Spi-1 ,Parabiosis ,Immunology ,Central nervous system ,Mice, Transgenic ,Biology ,DENDRITIC CELLS ,immunology [Monocytes] ,03 medical and health sciences ,Immune system ,Proto-Oncogene Proteins ,medicine ,Animals ,metabolism [Proto-Oncogene Proteins] ,HEMATOPOIETIC STEM-CELLS ,ddc:610 ,Transcription factor ,Science & Technology ,immunology [Central Nervous System] ,Macrophages ,MICROGLIAL CELLS ,physiology [Macrophages] ,Hematopoietic Stem Cells ,physiology [Microglia] ,Mice, Inbred C57BL ,030104 developmental biology ,Neuroimmunology ,Microscopy, Fluorescence ,CHOROID-PLEXUS ,Trans-Activators ,genetics [Proto-Oncogene Proteins] - Abstract
Perivascular, subdural meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It was assumed that they have a high turnover from blood-borne monocytes. However, using parabiosis and fate-mapping approaches in mice, we found that CNS macrophages arose from hematopoietic precursors during embryonic development and established stable populations, with the notable exception of choroid plexus macrophages, which had dual origins and a shorter life span. The generation of CNS macrophages relied on the transcription factor PU.1, whereas the MYB, BATF3 and NR4A1 transcription factors were not required.
- Published
- 2016
38. Development and Maintenance of the Brain’s Immune Toolkit: Microglia and Non-Parenchymal Brain Macrophages
- Abstract
Microglia and non-parenchymal macrophages located in the perivascular space, the meninges and the choroid plexus are independent immune populations that play vital roles in brain development, homeostasis, and tissue healing. Resident macrophages account for a significant proportion of cells in the brain and their density remains stable throughout the lifespan thanks to constant turnover. Microglia develop from yolk sac progenitors, later evolving through intermediate progenitors in a fine-tuned process in which intrinsic factors and external stimuli combine to progressively sculpt their cell type-specific transcriptional profiles. Recent evidence demonstrates that non-parenchymal macrophages are also generated during early embryonic development. In recent years, the development of powerful fate mapping approaches combined with novel genomic and transcriptomic methodologies have greatly expanded our understanding of how brain macrophages develop and acquire specialized functions, and how cell population dynamics are regulated. Here, we review the transcription factors, epigenetic remodeling, and signaling pathways orchestrating the embryonic development of microglia and non-parenchymal macrophages. Next, we describe the dynamics of the macrophage populations of the brain and discuss the role of progenitor cells, to gain a better understanding of their functions in the healthy and diseased brain. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 561-579, 2018
- Published
- 2018
39. Development and Maintenance of the Brain’s Immune Toolkit: Microglia and Non-Parenchymal Brain Macrophages
- Abstract
Microglia and non-parenchymal macrophages located in the perivascular space, the meninges and the choroid plexus are independent immune populations that play vital roles in brain development, homeostasis, and tissue healing. Resident macrophages account for a significant proportion of cells in the brain and their density remains stable throughout the lifespan thanks to constant turnover. Microglia develop from yolk sac progenitors, later evolving through intermediate progenitors in a fine-tuned process in which intrinsic factors and external stimuli combine to progressively sculpt their cell type-specific transcriptional profiles. Recent evidence demonstrates that non-parenchymal macrophages are also generated during early embryonic development. In recent years, the development of powerful fate mapping approaches combined with novel genomic and transcriptomic methodologies have greatly expanded our understanding of how brain macrophages develop and acquire specialized functions, and how cell population dynamics are regulated. Here, we review the transcription factors, epigenetic remodeling, and signaling pathways orchestrating the embryonic development of microglia and non-parenchymal macrophages. Next, we describe the dynamics of the macrophage populations of the brain and discuss the role of progenitor cells, to gain a better understanding of their functions in the healthy and diseased brain. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 561-579, 2018
- Published
- 2018
40. Development and Maintenance of the Brain’s Immune Toolkit: Microglia and Non-Parenchymal Brain Macrophages
- Abstract
Microglia and non-parenchymal macrophages located in the perivascular space, the meninges and the choroid plexus are independent immune populations that play vital roles in brain development, homeostasis, and tissue healing. Resident macrophages account for a significant proportion of cells in the brain and their density remains stable throughout the lifespan thanks to constant turnover. Microglia develop from yolk sac progenitors, later evolving through intermediate progenitors in a fine-tuned process in which intrinsic factors and external stimuli combine to progressively sculpt their cell type-specific transcriptional profiles. Recent evidence demonstrates that non-parenchymal macrophages are also generated during early embryonic development. In recent years, the development of powerful fate mapping approaches combined with novel genomic and transcriptomic methodologies have greatly expanded our understanding of how brain macrophages develop and acquire specialized functions, and how cell population dynamics are regulated. Here, we review the transcription factors, epigenetic remodeling, and signaling pathways orchestrating the embryonic development of microglia and non-parenchymal macrophages. Next, we describe the dynamics of the macrophage populations of the brain and discuss the role of progenitor cells, to gain a better understanding of their functions in the healthy and diseased brain. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 561-579, 2018
- Published
- 2018
41. Development and Maintenance of the Brain’s Immune Toolkit: Microglia and Non-Parenchymal Brain Macrophages
- Author
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Lopez-Atalaya, Jose P., Askew, Katharine E., Sierra Saavedra, Amanda, Gomez-Nicola, Diego, Ministerio de Economía y Competitividad (España), Eusko Jaurlaritza, Fundación BBVA, European Commission, Agencia Estatal de Investigación (España), Alzheimer's Research UK, Leverhulme Trust, and Medical Research Council (UK)
- Subjects
natural genetic-variation ,neural stem ,cns myeloid cells ,epigenetic heterogeneity ,Macrophages ,Brain ,microglia ,progenitor ,self-renewal ,tissue-resident macrophages ,hematopoietic stem-cells ,Animals ,Humans ,central-nervous-system ,adult brain ,development ,yolk-sac ,transcription factor ,lineage - Abstract
Microglia and non-parenchymal macrophages located in the perivascular space, the meninges and the choroid plexus are independent immune populations that play vital roles in brain development, homeostasis, and tissue healing. Resident macrophages account for a significant proportion of cells in the brain and their density remains stable throughout the lifespan thanks to constant turnover. Microglia develop from yolk sac progenitors, later evolving through intermediate progenitors in a fine-tuned process in which intrinsic factors and external stimuli combine to progressively sculpt their cell type-specific transcriptional profiles. Recent evidence demonstrates that non-parenchymal macrophages are also generated during early embryonic development. In recent years, the development of powerful fate mapping approaches combined with novel genomic and transcriptomic methodologies have greatly expanded our understanding of how brain macrophages develop and acquire specialized functions, and how cell population dynamics are regulated. Here, we review the transcription factors, epigenetic remodeling, and signaling pathways orchestrating the embryonic development of microglia and non-parenchymal macrophages. Next, we describe the dynamics of the macrophage populations of the brain and discuss the role of progenitor cells, to gain a better understanding of their functions in the healthy and diseased brain., Contract grant sponsor: Spanish Ministry of Economy and Competitiveness (MINECO) with European Regional Develop-ment Fund (ERDF) funds; contract grant numbers: BFU2015-66689, RYC-2013-12817.Contract grant sponsor: BBVA Foundation and a Basque Government; contract grant number: PI_2016_1_0011.Contract grant sponsor: “Ramon y Cajal” and European Social Fund (ESF) and national resources (MINEICO-AEI); contractgrant number: RYC-2015-18056.Contract grant sponsor: MINECO co-financed by the EuropeanRegional Development Fund (ERDF); contract grant number:SAF2014-60233-JIN.Contract grant sponsor: Instituto de Neurociencias is a “Centre ofExcellence Severo Ochoa”; contract grant number: SEV-2013-0317.Contract grant sponsor: Medical Research Council, Alzheimer’s Research UK and The Leverhulme Trust.
- Published
- 2018
42. Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates
- Author
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Geetanjali Sharma, Wallace B. Baze, Fortunato Ferrara, Tracey L. Smith, Richard L. Sidman, Erkki Koivunen, Daniela I. Staquicini, Patrick W. Hanley, Sara D'Angelo, Kirstin F. Barnhart, Serena Marchiò, Renata Pasqualini, Christy A. Tarleton, Wadih Arap, Akihiko Kuniyasu, Katja Karjalainen, Diana E. Jaalouk, B. K. Chaffee, Hagop M. Kantarjian, Jorge E. Cortes, and Biochemistry and Biotechnology
- Subjects
0301 basic medicine ,INTERLEUKIN-11 RECEPTOR ,Lymphoma ,Drug Evaluation, Preclinical ,Drug resistance ,Pharmacology ,REGULATOR GRP78/BIP ,ACTIVATION ,Mice ,Molecular Targeted Therapy ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,media_common ,Leukemia ,ENDOPLASMIC-RETICULUM CHAPERONE ,UNFOLDED PROTEIN RESPONSE ,Bone metastasis ,Myeloid leukemia ,3. Good health ,PROSTATE-CANCER ,LIGAND-DIRECTED THERAPY ,317 Pharmacy ,Molecular Medicine ,Drug ,Primates ,Cell Survival ,media_common.quotation_subject ,ACUTE MYELOID-LEUKEMIA ,Article ,03 medical and health sciences ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,DRUG-RESISTANCE ,business.industry ,United States Food and Drug Administration ,Investigational New Drug ,medicine.disease ,Macaca mulatta ,United States ,Rats ,Clinical trial ,Macaca fascicularis ,030104 developmental biology ,Peptidomimetics ,business - Abstract
Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.
- Published
- 2018
43. A molecular roadmap of the AGM region reveals BMP ER as a novel regulator of HSC maturation
- Author
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McGarvey, Alison C., Rybtsov, Stanislav, Souilhol, Celine, Tamagno, Sara, Rice, Ritva, Hills, David, Godwin, Duncan, Rice, David, Tomlinson, Simon R., Medvinsky, Alexander, Clinicum, University of Helsinki, David Paul Cracroft Rice / Principal Investigator, and HUS Head and Neck Center
- Subjects
REACTOME PATHWAY KNOWLEDGEBASE ,EMERGENCE ,animal structures ,BLOOD ,ENDOTHELIUM ,3121 General medicine, internal medicine and other clinical medicine ,embryonic structures ,MOUSE EMBRYO ,HEMATOPOIETIC STEM-CELLS ,YOLK-SAC ,FETAL LIVER ,SPECIFICATION ,GENE-EXPRESSION - Abstract
In the developing embryo, hematopoietic stem cells (HSCs) emerge from the aorta-gonad-mesonephros (AGM) region, but the molecular regulation of this process is poorly understood. Recently, the progression from E9.5 to E10.5 and polarity along the dorso-ventral axis have been identified as clear demarcations of the supportive HSC niche. To identify novel secreted regulators of HSC maturation, we performed RNA sequencing over these spatiotemporal transitions in the AGM region and supportive OP9 cell line. Screening several proteins through an ex vivo reaggregate culture system, we identify BMP ER as a novel positive regulator of HSC development. We demonstrate that BMP ER is associated with BMP signaling inhibition, but is transcriptionally induced by BMP4, suggesting that BMP ER contributes to the precise control of BMP activity within the AGM region, enabling the maturation of HSCs within a BMP-negative environment. These findings and the availability of our transcriptional data through an accessible interface should provide insight into the maintenance and potential derivation of HSCs in culture.
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- 2017
44. Cell type of origin dictates the route to pluripotency
- Author
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Sue Mei Lim, Keshav Faye-Chauhan, Christian M. Nefzger, Joseph Chen, Jaber Firas, Anja S Knaupp, Sam Buckberry, Jacob M. Paynter, Owen J. L. Rackham, Ryan Lister, Brenda Williams, Enrico Petretto, Xiaodong Liu, Jose M. Polo, Fernando J. Rossello, Sara Alaei, Mirana Ramialison, David R. Powell, Jahnvi Pflueger, and Susan K. Nilsson
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0301 basic medicine ,EXPRESSION ,keratinocytes ,Cell type ,induced pluripotent stem cells ,Cell ,EGR1 ,Biology ,MOUSE ,Universal model ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,IPS CELLS ,MARKERS ,neutrophils ,fibroblasts ,medicine ,Animals ,Humans ,HEMATOPOIETIC STEM-CELLS ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,Early Growth Response Protein 1 ,transcriptional dynamics ,Science & Technology ,Mesenchymal stem cell ,reprogramming ,Cell Biology ,Cellular Reprogramming ,Flow Cytometry ,MASS CYTOMETRY ,Cell identity ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,SOMATIC-CELLS ,Egr1 ,MOLECULAR ROADMAP ,Octamer Transcription Factor-3 ,Reprogramming ,Life Sciences & Biomedicine - Abstract
Summary: Our current understanding of induced pluripotent stem cell (iPSC) generation has almost entirely been shaped by studies performed on reprogramming fibroblasts. However, whether the resulting model universally applies to the reprogramming process of other cell types is still largely unknown. By characterizing and profiling the reprogramming pathways of fibroblasts, neutrophils, and keratinocytes, we unveil that key events of the process, including loss of original cell identity, mesenchymal to epithelial transition, the extent of developmental reversion, and reactivation of the pluripotency network, are to a large degree cell-type specific. Thus, we reveal limitations for the use of fibroblasts as a universal model for the study of the reprogramming process and provide crucial insights about iPSC generation from alternative cell sources. : Nefzger et al. find that the molecular reprogramming trajectories of fibroblasts, neutrophils, and keratinocytes have a cell-type-specific component that only fully converges in induced pluripotent stem cells. The authors also identify universal changes shared by all three cell types, including two transcriptional waves and a conserved transcriptional program involving Egr1 downregulation. Keywords: reprogramming, induced pluripotent stem cells, fibroblasts, neutrophils, keratinocytes, transcriptional dynamics, Egr1
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- 2017
45. Immuno-miRs
- Subjects
KAPPA-B PATHWAY ,DOWN-REGULATION ,microRNA ,T cell ,differentiation ,MULTIPLE-SCLEROSIS ,UP-REGULATION ,TH1 RESPONSES ,LINEAGE DIFFERENTIATION ,ageing ,MICRORNA SIGNATURES ,activation ,HEMATOPOIETIC STEM-CELLS ,MESSENGER-RNA ,GENE-EXPRESSION - Abstract
MicroRNAs (miRNAs) are instrumental to many aspects of immunity, including various levels of T-cell immunity. Over the last decade, crucial immune functions were shown to be regulated by specific miRNAs. These immuno-miRs' regulate generic cell biological processes in T cells, such as proliferation and apoptosis, as well as a number of T-cell-specific features that are fundamental to the development, differentiation and function of T cells. In this review, we give an overview of the current literature with respect to the role of miRNAs at various stages of T-cell development, maturation, differentiation, activation and ageing. Little is known about the involvement of miRNAs in thymic T-cell development, although miR-181a and miR-150 have been implicated herein. In contrast, several broadly expressed miRNAs including miR-21, miR-155 and miR-17 similar to 92, have now been shown to regulate T-cell activation. Other miRNAs, including miR-146a, show a more T-cell-subset-specific expression pattern and are involved in the regulation of processes unique to that specific T-cell subset. Importantly, differences in the miRNA target gene repertoires of different T-cell subsets allow similar miRNAs to control different T-cell-subset-specific functions. Interestingly, several of the here described immuno-miRs have also been implicated in T-cell ageing and there are clear indications for causal involvement of miRNAs in immunosenescence. It is concluded that immuno-miRs have a dynamic regulatory role in many aspects of T-cell differentiation, activation, function and ageing. An important notion when studying miRNAs in relation to T-cell biology is that specific immuno-miRs may have quite unrelated functions in closely related T-cell subsets.
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- 2015
46. A stromal cell free culture system generates mouse pro-T cells that can reconstitute T-cell compartments in vivo
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Gehre Nadine, Nusser Anja, von Muenchow Lilly, Tussiwand Roxane, Engdahl Corinne, Capoferri Giuseppina, Bosco Nabil, Ceredig Rhodri, and Rolink Antonius G
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CD3 Complex ,Receptors, Antigen, T-Cell, alpha-beta ,repopulating ability ,Cell Culture Techniques ,lineage commitment ,hematopoietic stem-cells ,T-Lymphocytes, Regulatory ,bm transplantation ,natural-killer-cell ,bone-marrow-transplantation ,Mice ,Antigens, CD ,delta-like 4 ,Animals ,Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Mice, Inbred BALB C ,Precursor Cells, T-Lymphoid ,Calcium-Binding Proteins ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,immune reconstitution ,lymphopenia ,t-cell development ,c-kit ,Female ,Stromal Cells ,notch ligand delta-like 4 (dl4) ,treg cell ,Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor ,deficiency syndrome aids ,cord blood-cells - Abstract
T-cell lymphopenia following BM transplantation or diseases such as AIDS result in immunodeficiency. Novel approaches to ameliorate this situation are urgently required. Herein, we describe a novel stromal cell free culture system in which Lineage(-)Sca1(+)c-kit(+) BM hematopoietic progenitors very efficiently differentiate into pro-T cells. This culture system consists of plate-bound Delta-like 4 Notch ligand and the cytokines SCF and IL-7. The pro-T cells developing in these cultures express CD25, CD117, and partially CD44; express cytoplasmic CD3 epsilon; and have their TCR locus partially D-J rearranged. They could be expanded for over 3 months and used to reconstitute the T-cell compartments of sublethally irradiated T-cell-deficient CD3 epsilon(-/-) mice or lethally irradiated WT mice. Pro-T cells generated in this system could partially correct the T-cell lymphopenia of pre-T-/- mice. However, reconstituted CD3 epsilon(-/-) mice suffered from a wasting disease that was prevented by co-injection of purified CD4(+) CD25(high) WT Treg cells. In a T-cell-sufficient or T-lymphopenic setting, the development of disease was not observed. Thus, this in vitro culture system represents a powerful tool to generate large numbers of pro-T cells for transplantation and possibly with clinical applications.
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- 2015
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47. Clonal heterogeneity as a driver of disease variability in the evolution of myeloproliferative neoplasms
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LEUKEMIC TRANSFORMATION ,GAIN-OF-FUNCTION ,BONE-MARROW ,ESSENTIAL THROMBOCYTHEMIA ,HEMATOPOIETIC STEM-CELLS ,MYELOID METAPLASIA ,MURINE MODEL ,MOUSE MODEL ,POLYCYTHEMIA-VERA ,TYROSINE KINASE JAK2 - Abstract
Myeloproliferative neoplasms (MPNs) are clonal hematological diseases in which cells of the myelo-erythroid lineage are overproduced and patients are predisposed to leukemic transformation. Hematopoietic stem cells are the suspected disease-initiating cells, and these cells must acquire a clonal advantage relative to nonmutant hematopoietic stem cells to perpetuate disease. In 2005, several groups identified a single gain-of-function point mutation in JAK2 that associated with the majority of MPNs, and subsequent studies have led to a comprehensive understanding of the mutational landscape in MPNs. However, confusion still exists as to how a single genetic aberration can be associated with multiple distinct disease entities. Many explanations have been proposed, including JAK2V617F homozygosity, individual patient heterogeneity, and the differential regulation of downstream JAK2 signaling pathways. Several groups have made knock-in mouse models expressing JAK2V617F and have observed divergent phenotypes, each recapitulating some aspects of disease. Intriguingly, most of these models do not observe a strong hematopoietic stem cell self-renewal advantage compared with wild-type littermate controls, raising the question of how a clonal advantage is established in patients with MPNs. This review summarizes the current molecular understanding of MPNs and the diversity of disease phenotypes and proposes that the increased proliferation induced by JAK2V617F applies a selection pressure on the mutant clone that results in highly diverse clonal evolution in individuals. (C) 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.
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- 2014
48. Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy
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Charles R. M. Bangham and Heather A Niederer
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Genotype ,LIGATION-MEDIATED PCR ,Genetic enhancement ,viruses ,Virus Integration ,Genetic Vectors ,lcsh:QR1-502 ,Review ,Vectors in gene therapy ,SEVERE COMBINED IMMUNODEFICIENCY ,lcsh:Microbiology ,gammaretroviral vector ,Retrovirus ,Virology ,medicine ,HUMAN GENOME ,Humans ,HEMATOPOIETIC STEM-CELLS ,Vector (molecular biology) ,Cell Proliferation ,Recombination, Genetic ,Severe combined immunodeficiency ,Science & Technology ,biology ,T-CELL LEUKEMIA ,VIRUS TYPE-1 HTLV-1 ,Genetic Variation ,Genetic Therapy ,Provirus ,medicine.disease ,biology.organism_classification ,gene therapy ,Integrase ,LENTIVIRAL VECTOR INTEGRATION ,CHRONIC GRANULOMATOUS-DISEASE ,Tumor Virus Infections ,Infectious Diseases ,Retroviridae ,HTLV-1 ,TRANSCRIPTION START SITES ,Chronic Disease ,biology.protein ,integration site ,Life Sciences & Biomedicine ,INSERTIONAL MUTAGENESIS ,Retroviridae Infections - Abstract
Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety.
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- 2014
49. Whole-exome sequencing identifies novel candidate predisposition genes for familial polycythemia vera
- Abstract
Background: Polycythemia vera (PV), characterized by massive production of erythrocytes, is one of the myeloproliferative neoplasms. Most patients carry a somatic gain-of-function mutation in JAK2, c.1849G > T (p.Val617Phe), leading to constitutive activation of JAK-STAT signaling pathway. Familial clustering is also observed occasionally, but high-penetrance predisposition genes to PV have remained unidentified. Results: We studied the predisposition to PV by exome sequencing (three cases) in a Finnish PV family with four patients. The 12 shared variants (maximum allowed minor allele frequency G (p.Phe418Leu) in ZXDC, c.1931C > G (p.Pro644Arg) in ATN1, and c.701G > A (p.Arg234Gln) in LRRC3. We also observed a rare, predicted benign germline variant c.2912C > G (p.Ala971Gly) in BCORL1 in all four patients. Somatic mutations in BCORL1 have been reported in myeloid malignancies. We further screened the variants in eight PV patients in six other Finnish families, but no other carriers were found. Conclusions: Exome sequencing provides a powerful tool for the identification of novel variants, and understanding the familial predisposition of diseases. This is the first report on Finnish familial PV cases, and we identified three novel candidate variants that may predispose to the disease.
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- 2017
50. Structure and Functions of Blood Vessels and Vascular Niches in Bone
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Ramasamy, Saravana K., Medical Research Council (MRC), and Wellcome Trust
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lcsh:Internal medicine ,Science & Technology ,EARLY MESENCHYMAL PROGENITORS ,ENERGY-METABOLISM ,MINERAL METABOLISM ,Cell Biology ,Review Article ,MICE LACKING ,ENDOTHELIAL-CELLS ,MARROW NICHE ,ANGIOGENESIS ,Cell & Tissue Engineering ,STROMAL CELLS ,PERIVASCULAR NICHE ,HEMATOPOIETIC STEM-CELLS ,lcsh:RC31-1245 ,Life Sciences & Biomedicine - Abstract
Bone provides nurturing microenvironments for an array of cell types that coordinate important physiological functions of the skeleton, such as energy metabolism, mineral homeostasis, osteogenesis, and haematopoiesis. Endothelial cells form an intricate network of blood vessels that organises and sustains various microenvironments in bone. The recent identification of heterogeneity in the bone vasculature supports the existence of multiple vascular niches within the bone marrow compartment. A unique combination of cells and factors defining a particular microenvironment, supply regulatory signals to mediate a specific function. This review discusses recent developments in our understanding of vascular niches in bone that play a critical role in regulating the behaviour of multipotent haematopoietic and mesenchymal stem cells during development and homeostasis.
- Published
- 2017
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