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Atherosclerosis (AS) is a chronic inflammatory disease of arteries fueled by lipids. It is a major cause of cardiovascular morbidity and mortality. Mesenchymal stem cells have been used for the treatment of atherosclerotic lesions. Adipose-derived stem cells (ADSCs) have been shown to regulate the activation state of macrophages and exhibit anti-inflammatory capabilities. However, the effect of allogeneic ADSCs in the treatment of AS have not been investigated. In this study, the early treatment effect and preliminary mechanism analysis of allogeneic rabbit ADSCs intravenous transplantation were investigated in a high-fat diet rabbit model. The polarization mechanism of rabbit ADSCs on the macrophage was further analyzed in vitro. Compared with the model group, blood lipid levels declined, the plaque area, oxidized low-density lipoprotein (ox-LDL) uptake, scavenger receptor A1 and cluster of differentiation (CD) 36 levels were all significantly reduced, and the accumulation of inflammatory M1 macrophages, apoptosis, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression were decreased. The endothelial cells (CD31), M2 macrophages, IL-10 and the transforming growth factor (TGF)-β levels increased. In vitro, ADSCs can promote the M1 macrophage phenotypic switch toward the M2 macrophage through their secreted exosomes, and the main mechanism includes increasing arginase 1 expression and IL-10 secretion, declining inducible nitric oxide synthase (iNOS) expression and TNF-α secretion, and activating the STAT6 pathway. Therefore, allogeneic rabbit ADSC transplantation can transmigrate to the aortic atherosclerotic plaques and show a good effect in lowering blood lipids and alleviating atherosclerotic plaque in the early stage of AS by inhibiting ox-LDL uptake, inflammatory response, and endothelial damage.

Mouse bone marrow mesenchymal stem cells (mBM-MSCs) are important for preclinical tissue regeneration and repair studies. In the present study, we isolated mBM-MSCs using three easy-to-perform methods (whole bone marrow-adherent culture, density-gradient centrifugation, and bone digestion), and then compared the morphology, proliferation, differentiation, and paracrine factor profiles of the isolated mBM-MSCs. Of these three isolation methods, the bone digestion method resulted in the highest quantity of mBM-MSCs with high growth potential and moderate differentiation. Conversely, the mBM-MSCs isolated through the whole bone marrow-adherent method exhibited the lowest potency for proliferation and differentiation. The differentially expressed factors between mBM-MSCs were primarily those involved in immune responses. The highly expressed secreted factors included cytokines/members of the chemokine family, growth factors, and protein binding/proteinase activity. These findings provide a fundamental reference for development of MSC isolation methods., (© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The transplantation of bone marrow-derived mesenchymal stem cells (BMMSCs) alleviates neuropathology and improves cognitive deficits in animal models with Alzheimer's disease. However, the underlying mechanism remains undefined. Based on meta-analysis and comprehensive review, high-profile studies support the theory that transplanted BMMSCs activate autophagy, as evidenced by the expression levels of signal molecules such as Beclin-1, Atg5, LC3-II, and mTOR. Functional autophagy mitigates neuronal apoptosis, which is reflected by the alterations of IAPs, Bcl-2, caspase-3, and so forth. Moreover, the transplantation of BMMSCs can decrease aberrant amyloid-beta peptides as well as tau aggregates, inhibit neuroinflammation, and stimulate synaptogenesis. There is a signal crosstalk between autophagy and apoptosis, which may be regulated to produce synergistic effect on the preconditioning of stem cells. Forasmuch, the therapeutic effect of transplanted BMMSCs can be enhanced by autophagy and/or apoptosis modulators., (© 2022. The Author(s).)

Glucocorticoids induce cellular senescence, including of stem/progenitor cells in the bone marrow of growing long bone, which leads to bone loss in glucocorticoid-induced osteoporosis. There is no specific drug available to treat this disease. Clearance of senescent cells has been reported to be an effective therapy for osteoporosis. LepR + cells in the bone marrow are the key kind of stem/progenitor cells conducive to bone remodeling in adulthood. Here, we show that glucocorticoids induce cellular senescence, demonstrated by increased activity of senescence-associated β-galactosidase (SA-βGal + ) cells and simultaneous upregulation of coimmunofluorescence staining of p16 INK4a with LepR in longitudinal femoral sections. We applied pulsed electromagnetic fields (PEMFs), which alleviated bone loss in glucocorticoid-induced osteoporosis mice. We found the increased accumulation of senescent LepR + cells in the bone marrow of adult mice after glucocorticoid treatment, and this could be counteracted by PEMFs. Moreover, PEMFs maintained type H vessel formation and osteogenesis. This process was modulated by the polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2) and its trimethylation of histone H3 on lysine 27 (H3K27me3). These results provide evidence that PEMFs alleviate bone loss induced by glucocorticoids by eliminating senescent cells, maintaining angiogenesis-osteogenesis coupling, and shedding light on the mechanisms, providing a potential method to treat glucocorticoid-induced osteoporosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Atherosclerosis (AS) is a complex disease caused in part by dyslipidemia and chronic inflammation. AS is associated with serious cardiovascular disease and remains the leading cause of mortality worldwide. Mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including AS. Human umbilical cord MSCs (UCSCs) have been used in cell therapy trials due to their ability to differentiate and proliferate. The present study aimed to investigate the effect of UCSCs treatment on atherosclerotic plaque formation and the progression of lesions in a high-fat diet rabbit model., Methods: Rabbits were fed a high-fat diet and then randomly divided into three groups: control, model, and treatment groups. Rabbits in the treatment group were injected with UCSCs (6 × 10 6 in 500 μL phosphate buffered saline) after 1 month of high-fat diet, once every 2 weeks, for 3 months. The model group was given PBS only. We analyzed serum biomarkers, used ultrasound and histopathology to detect arterial plaques and laser Doppler imaging to measure peripheral blood vessel blood filling, and analyzed the intestinal flora and metabolism., Results: Histological analysis showed that the aortic plaque area was significantly reduced in the treatment group. We also found a significant decrease in macrophage accumulation and apoptosis, an increase in expression of scavenger receptors CD36 and SRA1, a decrease in uptake of modified low-density protein (ox-LDL), and a decrease in levels of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α following UCSCs treatment. We also found that anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-β expression increased in the aorta atherosclerotic plaque of the treatment group. UCSCs treatment improved the early peripheral blood filling, reduced the serum lipid level, and inhibited inflammation progression by regulating the intestinal flora dysbiosis caused by the high-fat diet. More specifically, levels of the microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) were down-regulated in the treatment group., Conclusions: UCSCs treatment alleviated atherosclerotic plaque burden by reducing inflammation, regulating the intestinal flora and TMAO levels, and repairing the damaged endothelium., (© 2021. The Author(s).)

Senescence of bone marrow-derived mesenchymal stem cells (BMSCs) has been widely reported to be closely correlated with aging-related diseases, including osteoporosis (OP). Moreover, the beneficial functions of BMSCs decline with age, limiting their therapeutic efficacy in OP. In the present study, using RNA sequencing (RNA-Seq), we found that leucine-rich repeat containing 17 (LRRc17) expression in BMSCs was highly positively correlated with age. Therefore, we investigated whether LRRc17 knockdown could rejuvenate aged MSCs and increase their therapeutic efficacy in OP. Consistent with the RNA-Seq results, the protein expression of LRRc17 in senescent BMSCs was significantly increased, whereas LRRc17 knockdown inhibited cell apoptosis and reduced the expression of age-related proteins and G2 and S phase quiescence. Furthermore, LRRc17 knockdown shifted BMSCs from adipogenic to osteogenic differentiation, indicating the critical role of LRRc17 in BMSC senescence and differentiation. Additionally, similar to rapamycin (RAPA) treatment, LRRc17 knockdown activated mitophagy via inhibition of the mTOR/PI3K pathway, which consequently reduced mitochondrial dysfunction and inhibited BMSC senescence. However, the effects of LRRc17 knockdown were significantly blocked by the autophagy inhibitor hydroxychloroquine (HCQ), demonstrating that LRRc17 knockdown prevented BMSC senescence by activating mitophagy. In vivo, compared with untransfected aged mouse-derived BMSCs (O-BMSCs), O-BMSCs transfected with sh-LRRc17 showed effective amelioration of ovariectomy (OVX)-induced bone loss. Collectively, these results indicated that LRRc17 knockdown rejuvenated senescent BMSCs and thus enhanced their therapeutic efficacy in OP by activating autophagy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Mesenchymal stem cells (MSCs) have generated tremendous interest for treating various diseases due to their self-renewal and differentiation capacities. Many studies have demonstrated the immunoregulatory capability of MSCs; however, most of these studies were conducted with fetal bovine serum (FBS), which has an uncertain composition. In this study, we established a serum-free, xeno-free, completely chemically defined medium for the proliferation and expansion of rhesus monkey bone marrow (BM)-derived MSCs (rBMSCs) in vitro. The growth kinetics, characteristics, immunophenotype, and immunosuppressive abilities of rBMSCs grown in serum-free media (SFM) were evaluated and compared with those of cells grown in serum-containing media (SCM). Moreover, we employed RNA sequencing to evaluate the expression pattern of genes related to immune responses in both culture conditions. Compared to cells grown in SCM, rBMSCs grown in SFM exhibited better biological characteristics regarding cell proliferation and immunosuppressive abilities. Cells from both media types exhibited similar immunophenotypic expression patterns for CD29, CD34, CD45, HLA-DR, CD73, CD90, and CD105. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Gene Set Enrichment Analysis (GSEA) revealed that CXCL8 was downregulated by 4.1 fold in SFM-cultured rBMSCs compared with those in SCM. Furthermore, the mixed lymphocyte culture revealed that the proliferation activity and the expression levels of inflammatory factors of peripheral blood mononuclear cells (PBMCs) were significantly decreased after the addition of the CXCL8 neutralizing antibody, which was related to the elevated immunosuppressive abilities of SFM-suspended rBMSCs. These results suggest a possible cell culture method as well as immunoregulatory mechanisms for clinical cell therapies requiring nonanimal-derived components., (Copyright © 2018. Published by Elsevier B.V.)

Background: Alzheimer's disease is a neurodegenerative disorder. Therapeutically, a transplantation of bone marrow mesenchymal stem cells (BMMSCs) can play a beneficial role in animal models of Alzheimer's disease. However, the relevant mechanism remains to be fully elucidated. Main body: Subsequent to the transplantation of BMMSCs, memory loss and cognitive impairment were significantly improved in animal models with Alzheimer's disease (AD). Potential mechanisms involved neurogenesis, apoptosis, angiogenesis, inflammation, immunomodulation, etc. The above mechanisms might play different roles at certain stages. It was revealed that the transplantation of BMMSCs could alter some gene levels. Moreover, the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer's disease, which could be used to construct gene-specific patterns. Conclusions: Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models. Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect. The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Stem cell-based therapy serves a key role in clinical treatments, and mesenchymal stem cells (MSCs) have been widely used in clinical tumor therapy trials. In the present study, MSCs were isolated from umbilical cord (UC) and co-cultured with the lung cancer cell line H1299. The effects of UC-derived MSCs (UCMSCs) on H1299 cell invasion and proliferation were evaluated using a Matrigel-based Transwell assay and CCK8 assay, respectively. Apoptosis and cell cycle progression among H1299 cells were detected by flow cytometry, and kinase expression in H1299 cells was detected by western blotting. The results indicated that UCMSCs significantly inhibited H1299 cell invasion and significantly induced apoptosis of H1299 cells, but exhibited no effect on H1299 cell proliferation and cell cycle progression. It was also identified that H1299 cell expression of key kinases (AKT, phosphoinositide 3-kinase, signal transducer and activator of transcription 3 and mechanistic target of rapamycin) was significantly suppressed in the presence of UCMSCs. To the best of our knowledge, the present study demonstrates for the first time that UCMSCs have an anti-tumor effect against lung cancer cells, which may indicate that AKT/phosphoinositide 3-kinase/signal transducer and activator of transcription 3 signaling is important in the UCMSC-mediated regulation of H1299 cell functions. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalitis (EAE) is an inflammatory demyelinating disease, which served as a useful model providing considerable insights into the pathogenesis of multiple sclerosis (MS). Mouse bone marrow mesenchymal stem cells (mBM-MSC) were shown to have neuroprotection capabilities in EAE. Resveratrol is a small polyphenolic compound and possess therapeutic activity in various immune-mediated diseases. The sensitivity of mBM-MSCs to resveratrol was determined by an established cell-viability assay. Resveratrol-treated mBM-MSCs were also characterized with flow cytometry using MSC-specific surface markers and analyzed for their multiple differentiation capacities. EAE was induced in C57BL/6 mice by immunization with MOG35-55. Interferon gamma (IFN-γ)/tumor necrosis factor alpha (TNF-α) and interleukin-4 (IL-4)/interleukin-10 (IL-10), the hallmark cytokines that direct T helper type 1 (Th1) and Th2 development, were detected with enzyme-linked immunosorbent assay (ELISA). In vivo efficacy experiments showed that mBM-MSCs or resveratrol alone led to a significant reduction in clinical scores, and combined treatment resulted in even more prominent reduction. The combined treatment with mBM-MSCs and resveratrol enhanced the immunomodulatory effects, showing suppressed proinflammatory cytokines (IFN-γ, TNF-α) and increased anti-inflammatory cytokines (IL-4, IL-10). The combination of mBM-MSCs and resveratrol provides a novel potential experimental protocol for alleviating EAE symptoms. [ABSTRACT FROM AUTHOR]