mesenchymal stem cells

摘要： Postoperative cognitive dysfunction(POCD)is a common surgical complication.Diabetes mellitus(DM)increases risk of developing POCD after surgery.DM patients with POCD seriously threaten the quality of patients’life,however,the intrinsic mechanism is unclear,and the effective treatment is deficiency.Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD.In this study,we constructed a mouse model of DM by intraperitoneal injection of streptozotocin,and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion.We found that mouse models of DM-POCD exhibited the most serious cognitive impairment,as well as the most hippocampal neural stem cells(H-NSCs)loss and neurogenesis decline.Subsequently,we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells(iMSC-sEVs)might promote neurogenesis and restore cognitive function in patients with DM-POCD.iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery,and then once every 3 days for 1 month thereafter.Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs,and reversed cognitive impairment in mouse models of DM-POCD.Furthermore,miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs.We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis.As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C,while miR-486-5p can inhibit FoxO1 in NSCs.We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4,CDKN2C,and FoxO1 expression in H-NSCs.Collectively,these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD,the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.

摘要： Mesenchymal stem cells are multipotent stem cells that reside in many human tissues and organs.Mesenchymal stem cells are widely used in experimental and clinical regenerative medicine due to their capability to transdifferentiate into various lineages.However,when transplanted,they lose part of their multipotency and immunomodulatory properties,and most of them die after injection into the damaged tissue.In this review,we discuss the potential utility of melatonin in preserving mesenchymal stem cells’survival and function after transplantation.Melatonin is a pleiotropic molecule regulating critical cell functions including apoptosis,endoplasmic reticulum stress,and autophagy.Melatonin is also synthesized in the mitochondria where it reduces oxidative stress,the opening of the mitochondrial permeability transition pore and the downstream caspase activation,activates uncoupling proteins,and curtails the proinflammatory response.In addition,recent findings showed that melatonin also promotes the formation of tunneling nanotubes and the transfer of mitochondria between cells through the connecting tubules.As mitochondrial dysfunction is a primary cause of mesenchymal stem cells death and senescence and a critical issue for survival after transplantation,we propose that melatonin by favoring mitochondria functionality and their transfer through tunneling nanotubes from healthy to suffering cells could improve mesenchymal stem cellbased therapy in a large number of diseases for which basic and clinical trials are underway.

摘要： BACKGROUND Bronchopulmonary dysplasia(BPD)is not merely a chronic lung disease,but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current management strategies,limited progress has been made in reducing the BPD-related systemic damage.Meanwhile,although the protective effects of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)or their exosomes on hyperoxia-induced lung injury have been explored by many researchers,the underlying mechanism has not been addressed in detail,and few studies have focused on the therapeutic effect on systemic multiple organ injury.AIM To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung,heart,and kidney injuries and the underlying regulatory mechanisms.METHODS Neonatal rats were exposed to hyperoxia(80%O_(2)),treated with hUC-MSCs intratracheal(iT)or intraperitoneal(iP)on postnatal day 7,and harvested on postnatal day 21.The tissue sections of the lung,heart,and kidney were analyzed morphometrically.Protein contents of the bronchoalveolar lavage fluid(BALF),myeloper oxidase(MPO)expression,and malondialdehyde(MDA)levels were examined.Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay.A comparative transcriptomic analysis of differentially expressed genes(DEGs)in lung tissue was conducted via RNA-sequencing.Subsequently,we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses.RESULTS iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis(P<0.01,P<0.01,P<0.001,and P<0.05 for mean linear intercept,septal counts,vascular medial thickness index,and microvessel density respectively).Meanwhile,treatment with hUC-MSCs iT ameliorated right ventricular hypertrophy(for Fulton’s index,P<0.01),and relieved reduced nephrogenic zone width(P<0.01)and glomerular diameter(P<0.001)in kidneys.Among the beneficial effects,a reduction of BALF protein,MPO,and MDA was observed in hUC-MSCs groups(P<0.01,P<0.001,and P<0.05 respectively).Increased pro-inflammatory cytokines tumor necrosis factor-alpha,interleukin(IL)-1β,and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration(P<0.01,P<0.001,and P<0.05 respectively).In addition,we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia(P<0.05).Transcriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses,epithelial cell proliferation,and vasculature development.hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group.hUC-MSCs increased heme oxygenase-1(HO-1),JAK2,and STAT3 expression,and their phosphorylation in the lung,heart,and kidney(P<0.05).Remarkably,no significant difference was observed between the iT and iP administration.CONCLUSION iT hUC-MSCs administration ameliorates hyperoxia-induced lung,heart,and kidney injuries by activating HO-1 expression and JAK/STAT signaling.The therapeutic benefits of local iT and iP administration are equivalent.

摘要： Stem cell research is a promising area of transplantation and regenerative medicine with tremendous potential for improving the clinical treatment and diagnostic options across a variety of conditions and enhancing understanding of human development.Over the past few decades,mesenchymal stem cell(MSCs)studies have exponentially increased with a promising outcome.However,regardless of the huge investment and the research attention given to stem cell research,FDA approval for clinical use is still lacking.Amid the challenges confronting stem cell research as a cellbased product,there appears to be evidence of superior effect and heightened potential success in its expressed vesicles,exosomes,as cell-free products.In addition to their highly desirable intrinsic biologically unique structural,compositional,and morphological characteristics,as well as predominant physiochemical stability and biocompatibility properties,exosomes can also be altered to enhance their therapeutic capability or diagnostic imaging potential via physical,chemical,and biological modification approaches.More importantly,the powerful therapeutic potential and superior biological functions of exosomes,particularly,regarding engineered exosomes as cell-free products,and their utilization in a new generation of nanomedicine treatment,vaccination,and diagnosis platforms,brings hope of a change in the near future.This viewpoint discusses the trend of stem cell research and why stem cell-derived exosomes could be the game-changer.

摘要： BACKGROUND The effect of hypoxia on mesenchymal stem cells(MSCs)is an emerging topic in MSC biology.Although long non-coding RNAs(lncRNAs)and messenger RNAs(mRNAs)are reported to play a critical role in regulating the biological characteristics of MSCs,their specific expression and co-expression profiles in human placenta-derived MSCs(hP-MSCs)under hypoxia and the underlying mechanisms of lncRNAs in hP-MSC biology are unknown.AIM To reveal the specific expression profiles of lncRNAs in hP-MSCs under hypoxia and initially explored the possible mechanism of lncRNAs on hP-MSC biology.METHODS Here,we used a multigas incubator(92.5%N_(2),5%CO_(2),and 2.5%O_(2))to mimic the potential of hP-MSCs.RNA sequencing technology was applied to identify the exact expression profiles of lncRNAs and mRNAs under hypoxia.RESULTS We identified 289 differentially expressed lncRNAs and 240 differentially expressed mRNAs between the hypoxia and normoxia groups.Among them,the lncRNA SNHG16 was upregulated under hypoxia,which was also validated by reverse transcription-polymerase chain reaction.SNHG16 was confirmed to affect hP-MSC proliferation rates using a SNHG16 knockdown model.SNHG16 overexpression could significantly enhance the proliferation capacity of hP-MSCs,activate the PI3K/AKT pathway,and upregulate the expression of cell cycle-related proteins.CONCLUSION Our results revealed the specific expression characteristics of lncRNAs and mRNAs in hypoxiacultured hP-MSCs and that lncRNA SNHG16 can promote hP-MSC proliferation through the PI3K/AKT pathway.

摘要： the only treatment option for type 1 diabetes mellitus(T1DM)patients.Advances in diabetes care,such as insulin analogue therapies and new devices,including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease.They do not eliminate long-term complications and require several lifestyle sacrifices.A more ideal future therapy for T1DM,instead of supplementing the insufficient hormone production(a consequence ofβ-cell destruction),would also aim to stop or slow down the destructive autoimmune process.The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered.The goal of disease-modifying therapies is to target autoimmune mechanisms and preventβ-cell destruction.T1DM patients with betterβ-cell function have better glycemic control,reduced incidence of long-term complications and hypoglycemic episodes.Unfortunately,at the time symptomatic T1DM is diagnosed,most of the insulin secretingβcells are usually lost.Therefore,to maximize the salvageableβ-cell mass by disease-modifying therapies,detecting autoimmune markers in an early,optimally presymptomatic phase of T1DM is of great importance.Diseasemodifying therapies,such as immuno-and regenerative therapies are expected to take a relevant place in diabetology.The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.

摘要： Stem cell therapy is an attractive approach for recovery from myocardial infarction(MI)but faces the challenges of rapid diffusion and poor survival after transplantation.Here we developed an injectable collagen scaffold to promote the long-term retention of transplanted cells in chronic MI.Forty-five minipigs underwent left anterior descending artery(LAD)ligation and were equally divided into three groups 2 months later(collagen scaffold loading with human umbilical mesenchymal stem cell(hUMSC)group,hUMSC group,and placebo group(only phosphate-buffered saline(PBS)injection)).Immunofluorescence staining indicated that the retention of transplanted cells was promoted by the collagen scaffold.Echocardiography and cardiac magnetic resonance imaging(CMR)showed much higher left ventricular ejection fraction(LVEF)and lower infarct size percentage in the collagen/hUMSC group than in the hUMSC and placebo groups at 12 months after treatment.There were also higher densities of vWf-,α-sma-,and cTnT-positive cells in the infarct border zone in the collagen/cell group,as revealed by immunohistochemical analysis,suggesting better angiogenesis and more cardiomyocyte survival after MI.Thus,the injectable collagen scaffold was safe and effective on a large animal myocardial model,which is beneficial for constructing a favorable microenvironment for applying stem cells in clinical MI.

摘要： BACKGROUND Multipotent bone marrow stromal cells(BMSCs)are adult stem cells that form functional osteoblasts and play a critical role in bone remodeling.During aging,an increase in bone loss and reduction in structural integrity lead to osteoporosis and result in an increased risk of fracture.We examined age-dependent histological changes in murine vertebrae and uncovered that bone loss begins as early as the age of 1 mo.AIM To identify the functional alterations and transcriptomic dynamics of BMSCs during early bone loss.METHODS We collected BMSCs from mice at early to middle ages and compared their selfrenewal and differentiation potential.Subsequently,we obtained the transcriptomic profiles of BMSCs at 1 mo,3 mo,and 7 mo.RESULTS The colony-forming and osteogenic commitment capacity showed a comparable finding that decreased at the age of 1 mo.The transcriptomic analysis showed the enrichment of osteoblastic regulation genes at 1 mo and loss of osteogenic features at 3 mo.The BMSCs at 7 mo showed enrichment of adipogenic and DNA repair features.Moreover,we demonstrated that the WNT and MAPK signaling pathways were upregulated at 1 mo,followed by increased pro-inflammatory and apoptotic features.CONCLUSION Our study uncovered the cellular and molecular dynamics of bone aging in mice and demonstrated the contribution of BMSCs to the early stage of age-related bone loss.

摘要： Liver diseases caused by various factors have become a significant threat to publichealth worldwide. Liver transplantation has been considered as the only effectivetreatment for end-stage liver diseases;however, it is limited by the shortage ofdonor organs, postoperative complications, long-term immunosuppression, andhigh cost of treatment. Thus, it is not available for all patients. Recently,mesenchymal stem cells (MSCs) transplantation has been extensively explored forrepairing hepatic injury in various liver diseases. MSCs are multipotent adultprogenitor cells originated from the embryonic mesoderm, and can be found inmesenchymal tissues including the bone marrow, umbilical cord blood, adiposetissue, liver, lung, and others. Although the precise mechanisms of MSC transplantationremain mysterious, MSCs have been demonstrated to be able toprevent the progression of liver injury and improve liver function. MSCs can selfrenewby dividing, migrating to injury sites and differentiating into multiple celltypes including hepatocytes. Additionally, MSCs have immune-modulatoryproperties and release paracrine soluble factors. Indeed, the safety and effectivenessof MSC therapy for liver diseases have been demonstrated in animals.However, pre-clinical and clinical trials are largely required to confirm its safetyand efficacy before large scale clinical application. In this review, we will explorethe molecular mechanisms underlying therapeutic effects of MSCs on liverdiseases. We also summarize clinical advances in MSC-based therapies.

摘要： Inflammatory periodontal disease known as periodontitis is one of the most common conditions that affect human teeth and often leads to tooth loss.Due to the complexity of the periodontium,which is composed of several tissues,its regeneration and subsequent return to a homeostatic state is challenging with the therapies currently available.Cellular therapy is increasingly becoming an alternative in regenerative medicine/dentistry,especially therapies using mesenchymal stem cells,as they can be isolated from a myriad of tissues.Periodontal ligament stem cells(PDLSCs)are probably the most adequate to be used as a cell source with the aim of regenerating the periodontium.Biological insights have also highlighted PDLSCs as promising immunomodulator agents.In this review,we explore the state of knowledge regarding the properties of PDLSCs,as well as their therapeutic potential,describing current and future clinical applications based on tissue engineering techniques.