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Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future. [ABSTRACT FROM AUTHOR]

B-lymphocytopenia among myelosuppression is the most intractable side effect of chemotherapy. Here, we investigated ways to alleviate 5-fluorouracil-caused stress hematopoietic impairment. We found that intraperitoneally injected ASP (Angelica sinensis polysaccharides) (100 mg/kg per day), one main active ingredient of Angelica sinensis, for consecutive 7 days, significantly recovered mouse bone marrow pro-B and pre-B cells, reversed the capacity of CFU-PreB colony forming, thus alleviating B cell reduction in the spleen and peripheral blood, as well as ameliorating immunoglobin from spleen and serum. The mechanism is related to the protective effects of ASP on IL-7 producing cells, including perivascular Leptin+ and CXCL12+ mesenchymal stem and progenitor cells (MSPCs), thus promoting IL-7 production, and activating IL-7R-mediated STAT5, PI3K-AKT signaling, including survival signals and EBF1, PAX5 transcription factor expression. Additionally, ASP's IL-7 promoting effect was demonstrated to be associated with maintaining osteogenesis/adipogenesis balance of MSPCs via the NRF2 antioxidant pathway. Collectively, our findings indicate that ASP reverse stress B-lymphocytopenia via improving Nrf2 signaling, promoting IL-7 production in MSPCs, and subsequently maintaining survival, proliferation, and differentiation of B cell progenitors, which may represent a promising therapeutic strategy. [Display omitted] • Angelica Sinensis Polysaccharides restore 5-Fluorouracil-induced B-lymphocytopenia. • Angelica Sinensis Polysaccharides antagonize 5-Fluorouracil-caused mesenchymal progenitor oxidative stress via Nrf2 signaling, keeping osteogenic differentiation potential, protecting IL-7 producing cells. • Angelica Sinensis Polysaccharides reverse 5-Fluorouracil-induced decreased IL-7-IL-7R signaling, rescuing the proliferation, survival and differentiation of B cell progenitors. [ABSTRACT FROM AUTHOR]

Pre-eclampsia is thought to be a systemic disease of maternal endothelial cell dysfunctions. mi RNAs regulate various basic biological functions in cells, including stem cells. Mesenchymal stem cells exist in almost all tissues and are the key cellular source for tissue repair and regeneration. Our aims are to investigate whether mi RNAs regulate MSCs in fetal-maternal interfaces to influence the pathogenesis of pre-eclampsia. The differential expression of mi RNAs in decidua-derived mesenchymal stem cells of all patients with severe pre-eclampsia ( n = 20) and normal groups ( n = 20) was first screened by microarray analysis and validated by quantitative real-time PCR analysis. The integrated bioinformatics analysis showed that miR-16 showed the highest number of connections in the mi RNA GO network and the mi RNA gene network. Moreover, over-expressed miR-16 inhibited the proliferation and migration of decidua-derived mesenchymal stem cells and induced cell-cycle arrest by targeting cyclin E1. Interestingly, over-expression of miR-16 by decidua-derived mesenchymal stem cells reduced the ability of human umbilical vein endothelial cells to form blood vessels and reduced the migration of trophoblast cells. Furthermore, decidua-derived mesenchymal stem cell-expressed endothelial growth factor VEGF-A was involved in migration of trophoblast cells and human umbilical vein endothelial cells as well as tube and network formation. Importantly, the levels of cyclin E1 and VEGF-A were negatively correlated with the level of miR-16 expression in decidua-derived mesenchymal stem cells from the patients with severe pre-eclampsia. Together, these data suggest that the alteration of miR-16 expression in decidua-derived mesenchymal stem cells may be involved in the development of pre-eclampsia. [ABSTRACT FROM AUTHOR]

Background. An important feature of aging cells is the gradual loss of physiological integrity. As aging progresses, MSCs change preferring to differentiate toward adipocytes rather than osteoblasts. Oxidative stress accumulation is an important factor in age-related bone loss. Many experiments have demonstrated the good therapeutic effect of Ginsenoside (Rg1) on oxidative stress injury. In this study, we investigated the effect of Rg1 on the osteogenic-adipogenic differentiation balance of bone marrow mesenchymal stem cells (BMMSC). Objective. To analyze the potential application value of Rg1 in the treatment of senile osteoporosis. Methods. BMMSCs were isolated from healthy donors of different ages and identified based on isotype and by multi-differentiation induction. Rg1 was used to treat BMMSCs, The differentiation propensity was analyzed by induction of differentiation assay. Antioxidant capacity of BMMSCs as measured by oxidative stress product assay Related mechanism studies were confirmed by quantitative real-time reverse transcription-polymerase chain reaction (qRT‐PCR), immunofluorescence, western blotting, and inhibitor treatment. Moreover, Observation of the effects of Rg1 on aging BMMSCs under in vivo conditions by treatment of aged mice with Rg1 injections. Results. Rg1 treatment rescued age‐induced switch of BMMSCs differentiation fate in vitro. In elderly people, Rg1 markedly increased osteogenic differentiation of BMMSCs by decreasing oxidative stress, while inhibiting adipogenic differentiation. However, this effect was abolished in BMMSCs by an Nrf2-inhibitor. Notably, aging mice showed a reduction in adipocyte distribution in the bone marrow and a decrease in oxidative stress products after a 3-month period of Rg1 treatment. Conclusion. We have uncovered a novel function for Rg1 that involves attenuating bone loss via Nrf2 antioxidant signaling, which in turn may potentially be utilized as a therapeutic agent for improving osteogenic differentiation in aging BMMSCs. [ABSTRACT FROM AUTHOR]

Senescence limits the characteristics and functionality of mesenchymal stem cells (MSCs), thereby severely restricting their application in tissue engineering. Here, we investigated ways to prevent MSCs from entering a state of senescence. We found that Rg1, an extract of natural ginseng, can reduce the expression of senescence markers in cultured cells in vitro and in various tissues in vivo. Simultaneously, ginsenoside Rg1 improved the antioxidant capacity of cells, and the senescence-inhibiting and antioxidant effect of Rg1 were associated with the activation of the nuclear factor E2-related factor 2 (NRF2) signaling pathway. Furthermore, Rg1 may activate the NRF2 pathway by increasing the interaction between P62 and KEAP1through P62 upregulation and AKT activation. Taken together, our findings indicate that Rg1 prevents cell senescence via NRF2 and AKT, and activation of AKT or NRF2 may thus represent therapeutic targets for preventing cell senescence. [Display omitted] • Ginsenoside Rg1 improves the antioxidant capacity of cells. • Ginsenoside Rg1 ameliorates D-gal-induced senescence through activation of NRF2. • Ginsenoside Rg1 reduces NRF2 degradation by promoting the interaction of P62 with KEAP1. [ABSTRACT FROM AUTHOR]

Objectives. To demonstrate the effect of Ginsenoside Rg1 on the differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). Subsequently, a rational mechanism for the detection of Rg1 which affects mesenchymal stem cell differentiation was explored. Methods. Flow cytometry is used for cell identification. The differentiation ability of hBM-MSCs was studied by differentiation culture. SA-β-gal staining is used to detect cell senescence levels. Western blot and immunofluorescence were used to determine protein expression levels. RT-qPCR is used to detect mRNA expression levels. Results. Rg1 regulates the differentiation of hBM-MSCs. Differentiation culture analysis showed that Rg1 promoted cells to osteogenesis and chondrogenesis. Western blot results showed that Rg1 regulated the overactivation of the β-catenin signaling pathway and significantly adjusted the phosphorylation of GSK-3β. GSK-3β inhibitor (Licl) significantly increased Rg1-induced phosphorylation of GSK-3β, which in turn reduced Rg1-induced differentiation of hBM-MSCs. Conclusion. Ginsenoside Rg1 can reduce the excessive activation of the Wnt pathway in senescent cells by inhibiting the phosphorylation of GSK-3β and regulate the mesenchymal stem cell differentiation ability. [ABSTRACT FROM AUTHOR]

Objective. To preliminary explore the senescent dynamic changes of the bone marrow mesenchymal stem cells (BMMSCs) by human ageing and its possible mechanism. Methods. The bone marrows were harvested from healthy volunteers, and according to volunteers' age, these were divided into group A (≤25 years), group B (26-45 years), group C (46-65 years), and group D (>65 years). Totally, the bone marrows were extracted from the posterior superior iliac spine from volunteers under aseptic conditions. Diluted with isovolumic PBS, followed by centrifugation at 1×105/cm2, cells were cultured in a 5% CO2 incubator at 37°C. After three passages, surface marker identification of hBMMSCs was tested by flow cytometry (FCM), oil red O staining was used to observe the ability of osteogenic differentiation, alkaline phosphatase (ALP) staining and the levels of osteocalcin (OST) in the supernatants were used to observe the ability of adipogenic differentiation, senescence-associated β-galactosidase (SA-β-Gal) staining was used to detect the senescent BMSCs, the ability of BMSC proliferation was detected by cell counting kit-8 (CCK-8), the distribution of the cell cycle was analyzed by flow cytometry (FCM), and malondialdehyde (MDA) content, total glutathione peroxidase, total antioxidant capacity, and total superoxide dismutase (SOD) activity was analyzed using enzymatic assay. Results. The BMSCs highly expressed CD73 and CD90, but lowly expressed CD34 and CD19/CD14. With age, osteogenic differentiation was markedly increased and audiogenic differentiation was significantly decreased. The number of SA-β-gal-positive cells was significantly increased, the proliferation ability of hBMMSCs declined, the BMSCs were held in the G1 phase, the MDA level of BMSCs was significantly increased, and total glutathione peroxidase, total antioxidant capacity, and SOD activity significantly declined. Conclusions. With age, the aging BMSCs were intensified; the mechanism may be related to oxidative damage mediated aging-related pathways. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy can induce premature ovarian insufficiency (POI) and reduce fertility in young female patients. Currently, there is no effective therapy for POI. Human amnion-derived mesenchymal stem cells (hAD-MSCs) may be a promising seed cell for regenerative medicine. This study investigated the effects and mechanisms of hAD-MSC transplantation on chemotherapy-induced POI in rats. Methods: Chemotherapy-induced POI rat models were established by intraperitoneal injection of cyclophosphamide. Seventy-two female SD rats were randomly divided into control, POI, and hAD-MSC-treated groups. hAD-MSCs were labeled with PKH26 and injected into the tail veins of POI rats. To examine the underlying mechanisms, the differentiation of transplanted hAD-MSCs in the POI ovaries was analyzed by immunofluorescent staining. The in vitro expression of growth factors secreted by hAD-MSCs in hAD-MSC-conditioned media (hAD-MSC-CM) was analyzed by ELISA. Sixty female SD rats were divided into control, POI, and hAD-MSC-CM-treated groups, and hAD-MSC-CM was injected into the bilateral ovaries of POI rats. After hAD-MSC transplantation or hAD-MSC-CM injection, serum sex hormone levels, estrous cycles, ovarian pathological changes, follicle counts, granulosa cell (GC) apoptosis, and Bcl-2, Bax, and VEGF expression in ovaries were examined. Results: PKH26-labeled hAD-MSCs mainly homed to ovaries after transplantation. hAD-MSC transplantation reduced ovarian injury and improved ovarian function in rats with POI. Transplanted hAD-MSCs were only located in the interstitium of ovaries, rather than in follicles, and did not express the typical markers of oocytes and GCs, which are ZP3 and FSHR, respectively. hAD-MSCs secreted FGF2, IGF-1, HGF, and VEGF, and those growth factors were detected in the hAD-MSC-CM. hAD-MSC-CM injection improved the local microenvironment of POI ovaries, leading to a decrease in Bax expression and an increase in Bcl-2 and endogenous VEGF expression in ovarian cells, which inhibited chemotherapy-induced GC apoptosis, promoted angiogenesis and regulated follicular development, thus partly reducing ovarian injury and improving ovarian function in rats with POI. Conclusions: hAD-MSC transplantation can improve ovarian function in rats with chemotherapy-induced POI at least partly through a paracrine mechanism. The presence of a paracrine mechanism accounting for hAD-MSC-mediated recovery of ovarian function might be attributed to the growth factors secreted by hAD-MSCs. [ABSTRACT FROM AUTHOR]

Abstract To investigate the effect and mechanism of ginsenoside Rg1 antagonizing bone marrow stromal cells (BMSCs) aging, which contribute to the delaying senescence of hematopoietic cells in vitro and in vivo. Rg1 could reduce the effects of senility agent on BMSCs by decreasing the rate of SA-Gal positive cells, and increasing the proliferative ability of CCK8 cells. After BMNCs co-cultured with BMSCs which were treated by Rg1 in vitro, compared with BMNCs co-cultured with BMSCs from aging group, percentage of positive cell SA-Gal staining was decreased, the formation ability of CFU-Mix was enhanced, the proliferative ability was increased, and the apoptosis rate was decreased. In aging rat model, after treated with Rg1, the percentage of positive cell SA-Gal staining in BMSCs was significantly decreased, the proliferative ability was increased. After treated with Rg1, the percentage of positive cell SA-Gal staining in BMNCs was significantly decreased, the formation ability of CFU-Mix mixed colony was enhanced, ROS was decreased, and SOD activity was increased. Aging BMSCs could induce the senescence of BMNCs. Rg1 could antagonize the effect of d -gal on the aging of BMSCs both in vivo and in vitro, and restore the hematopoietic capacity of BMNCs through the different pathways. [ABSTRACT FROM AUTHOR]

Objectives This study was to investigate the effect and mechanism of low-intensity pulsed ultrasound ( LIPUS) on the proliferation of human amnion-derived mesenchymal stem cells ( hAD- MSCs). Methods Human amnion-derived mesenchymal stem cells were isolated from the amnion of term placentas and identified by flow cytometry and differentiation culture. Proliferation of hAD- MSCs was investigated by Cell Counting Kit-8, cell cycle and EdU assays. Western blotting was used to determine the protein expression levels. Results Human amnion-derived mesenchymal stem cells were successfully isolated from the amnion and identified as multipotent mesenchymal stem cells. Low-intensity pulsed ultrasound promoted the proliferation of hAD- MSCs. Cell cycle analysis showed that LIPUS promoted cells to enter S and G2/M phases from G0/G1 phase. Western blot results showed that LIPUS promoted the phosphorylation and activation of ERK1/2 and Akt and significantly upregulated expression of cyclin D1, cyclin E1, cyclin A2 and cyclin B1. ERK1/2 inhibitor (U0126) and PI3K inhibitor ( LY294002) significantly reduced LIPUS-induced phosphorylation of ERK1/2 and Akt, respectively, which in turn reduced the LIPUS-induced proliferation of hAD-MSCs. Conclusions Low-intensity pulsed ultrasound can promote the proliferation of hAD- MSCs, and ERK1/2 and PI3K-Akt signalling pathways may play important roles in this process. [ABSTRACT FROM AUTHOR]

Background Previous studies have demonstrated that biological aging has a negative influence on the therapeutic effects of mesenchymal stem cells (MSCs)-based therapy. Using a rat myocardial infarction (MI) model, we tested the hypothesis that silent mating type information regulation 2 homolog 1 (SIRT1) may ameliorate the phenotype and improve the function of aged MSCs and thus enhance the efficacy of aged MSCs-based therapy. Methods Sixty female rats underwent left anterior descending coronary artery ligation and were randomly assigned to receiving: intramyocardial injection of cell culture medium (DMEM group); SIRT1 overexpression vector-treated aged MSCs (SIRT1-aged MSCs group) obtained from aged male SD rats or empty vector-treated aged MSCs (vector-aged MSCs group). Another 20 sham-operated rats that underwent open-chest surgery without coronary ligation or any other intervention served as controls. Results SIRT1-aged MSC group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti-stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level. Conclusions Up-regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI as it relates to the amelioration of senescent phenotype and hence improved biological function of aged MSCs. [ABSTRACT FROM AUTHOR]

Problem Progesterone ( P4) plays a central role in the establishment and maintenance of pregnancy. It also has profound effects on the regulation of immune responses. Mesenchymal stem cells ( MSCs), which are thought to have the ability to modulate immunocyte activation, are present in human endometrium and deciduas and highly express progesterone receptor ( PR). Especially, during pregnancy, both P4 and MSCs are present and regulatively changed at the fetal-maternal interface, but the effect of P4 on the MSCs remains unknown. Therefore, in this study, we investigated the effects of P4 on the immunomodulatory ability of MSCs and the underlying mechanisms. Method of study Mesenchymal stem cells were obtained from human umbilical cords. The effects of P4 on the cell morphology, phenotype, proliferation, apoptosis, and expression levels of cytokine and protein were examined. Results Progesterone did not affect the phenotype, morphology, proliferation, and apoptosis of MSCs, but promoted the production of PGE2 and IL-6 in MSCs. Furthermore, the up-regulation of PGE2 and IL-6 was related to the activation of p38 and NF-κB. Conclusions Progesterone enhances immunomodulatory function of MSCs through up-regulation of PGE2 and IL-6. The data suggest that P4-regulated MSCs may play a crucial role in modulating the local immune balance of fetal-maternal interface. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We hypothesized that anoxic preconditioning (AP) could enhance the cardioprotective effect of mesenchymal stem cells (MSCs). Methods: Myocardial infarction (MI) was set up in Sprague–Dawley rats and left ventricles were randomly injected with the following: DMEM, MSCs and AP-MSCs. Cardiac function was assessed by echocardiography 4 weeks after transplantation, hematoxylin–eosin staining and Masson trichrome were performed subsequently. Results: Increased fractional shortening, ejection fraction and decreased infarct size were observed most obviously in AP-MSCs group, accompanied by increased arteriole density and cell survival. Conclusions: AP enhanced the capacity of MSCs to repair infarcted myocardium, attributable to increased cell survival and angiogenesis. [Copyright &y& Elsevier]