Bone regeneration for non-load-bearing defects remains a significant clinical challenge requiring advanced biomaterials and cellular strategies.Adiposederived mesenchymal stem cells(AD-MSCs)have garnered significant i...Bone regeneration for non-load-bearing defects remains a significant clinical challenge requiring advanced biomaterials and cellular strategies.Adiposederived mesenchymal stem cells(AD-MSCs)have garnered significant interest in bone tissue engineering(BTE)because of their abundant availability,minimally invasive harvesting procedures,and robust differentiation potential into osteogenic lineages.Unlike bone marrow-derived mesenchymal stem cells,AD-MSCs can be easily obtained in large quantities,making them appealing alternatives for therapeutic applications.This review explores hydrogels containing polymers,such as chitosan,collagen,gelatin,and hyaluronic acid,and their composites,tailored for BTE,and emphasizes the importance of these hydrogels as scaffolds for the delivery of AD-MSCs.Various hydrogel fabrication techniques and biocompatibility assessments are discussed,along with innovative modifications to enhance osteogenesis.This review also briefly outlines AD-MSC isolation methods and advanced embedding techniques for precise cell placement,such as direct encapsulation and three-dimensional bioprinting.We discuss the mechanisms of bone regeneration in the AD-MSC-laden hydrogels,including osteoinduction,vascularization,and extracellular matrix remodeling.We also review the preclinical and clinical applications of AD-MSC-hydrogel systems,emphasizing their success and limitations.In this review,we provide a comprehensive overview of AD-MSC-based hydrogel systems to guide the development of effective therapies for bone regeneration.展开更多
Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesi...Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways.Chronic alcohol consumption leads to neuroinflammation,brain damage,and impaired cognition.Evidence indicates that females are more vulnerable to alcohol-induced damage than males.While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions,their potential to counteract alcohol-induced brain damage remains unclear.In this study,we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice.Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer(^(18)F-FDG)when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice.Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation,cognitive dysfunction,and the conditioned rewarding effects of cocaine.MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration.In addition,mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes(e.g.,Socs3,Tnf,Mtor,and Atf6)in the brains of ethanol-treated female mice.These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation,cognitive dysfunction,and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.展开更多
Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms o...Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.展开更多
Mesenchymal stem cells(MSCs)are pluripotent stem cells isolated from human tissues.Due to their strong self-renewal capacity,pluripotency,and immunomodulatory properties,MSCs have garnered significant attention in cel...Mesenchymal stem cells(MSCs)are pluripotent stem cells isolated from human tissues.Due to their strong self-renewal capacity,pluripotency,and immunomodulatory properties,MSCs have garnered significant attention in cell therapy and tissue regeneration.However,cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation,making it crucial to develop interventions that delay or reverse the senescence process.From a traditional Chinese medicine perspective,senescence stems from spleen and stomach deficiency,kidney deficiency,and related factors;thus,medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy.Chinese medicine,characterized by low toxicity and multi-target,multi-functional properties,has become prominent in anti-senescence research.This paper examines the MSC senescence process by discussing its causes,characteristics,and mechanisms,then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence,facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.展开更多
Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplanta...Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.展开更多
BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention...BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention for its role in influencing their function,accessibility,and readiness for clinical use.AIM To identify the most suitable adipose source for MSC isolation and expansion for further applications.METHODS We isolated MSCs from solid adipose tissue and liposuction aspirates using the enzyme method.The MSCs were examined for their expansion using population doubling time,differentiation capacity using multilineage differentiation induction,surface markers using flow cytometry,and stability of chromosomes using the karyotyping method.Growth factors and cytokines in MSC-conditioned media were analyzed using the Luminex assay.RESULTS MSCs were isolated from solid adipose tissue and lipoaspirates and expanded from passage 0 to passage 2.All adipose-derived MSCs(AD-MSCs)exhibited the typical elongated,spindle-shaped morphology and comparable proliferation rate.They expressed positive surface markers(cluster of differentiation 73[CD73]:>97%,CD90:>98%,and CD105:>95%),and negative markers(<1%).All MSCs expressed similar levels of stemness genes(octamer-binding transcription factor 4,SRY-box 2,Krüppel-like factor,and MYC),colonyforming,and trilineage differentiation potential.Karyotyping analysis revealed normal chromosomal patterns in all samples,except one sample exhibiting a polymorphism(1qh+).Furthermore,the growth factors and cytokines of hepatocyte growth factor,vascular endothelial growth factor A,interleukin 6(IL-6),and IL-8 were detected in all AD-MSC conditioned media;but fibroblast growth factor-2 and keratinocyte growth factor were selectively expressed in conditioned media from solid or lipoaspirate AD-MSCs,respectively.CONCLUSION These findings indicate that AD-MSCs from both adipose sources possess all of the characteristic features of MSCs with source-specific secretome differences,which are suitable for further expansion and various clinical applications.展开更多
Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good m...Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.展开更多
Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in hu...Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in humans remain unclear,including cell viability,distribution,migration,and fate.Conventional cell tracing methods cannot be used in the clinic.The use of superparamagnetic iron oxide nanoparticles as contrast agents allows for the observation of transplanted cells using magnetic resonance imaging.In 2016,the National Medical Products Administration of China approved a new superparamagnetic iron oxide nanoparticle,Ruicun,for use as a contrast agent in clinical trials.In the present study,an acute hemi-transection spinal cord injury model was established in beagle dogs.The injury was then treated by transplantation of Ruicun-labeled mesenchymal stromal cells.The results indicated that Ruicunlabeled mesenchymal stromal cells repaired damaged spinal cord fibers and partially restored neurological function in animals with acute spinal cord injury.T2*-weighted imaging revealed low signal areas on both sides of the injured spinal cord.The results of quantitative susceptibility mapping with ultrashort echo time sequences indicated that Ruicun-labeled mesenchymal stromal cells persisted stably within the injured spinal cord for over 4 weeks.These findings suggest that magnetic resonance imaging has the potential to effectively track the migration of Ruicun-labeled mesenchymal stromal cells and assess their ability to repair spinal cord injury.展开更多
Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells en...Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.展开更多
Lupus nephritis(LN)is one of the most common and serious complications of systemic lupus erythematosus,which can lead to end-stage renal disease,and is an important cause of death in patients with systemic lupus eryth...Lupus nephritis(LN)is one of the most common and serious complications of systemic lupus erythematosus,which can lead to end-stage renal disease,and is an important cause of death in patients with systemic lupus erythematosus.Treatment options include glucocorticoids,immunosuppressive agents and the addition of biologics.Recently,the therapeutic role of mesenchymal stem cells(MSCs)in LN has received extensive attention worldwide.MSCs can suppress autoimmunity,alleviate proteinuria and restore renal function by modulating the functions of various immune cells and reducing the secretion of inflammatory cytokines.Several clinical trials have investigated MSC treatment in LN with promising but sometimes inconsistent outcomes.This review summarizes the sources of MSCs and mechanisms in immunoregulation.Furthermore,it examines clinical trials evaluating the efficacy,safety,and limitations of MSC therapy in LN.By highlighting advances and ongoing challenges,this review underscores the potential of MSCs for LN treatment.More large-scale randomized controlled trials are needed to support the effectiveness of this therapy and pave the way for personalized and combinatorial therapeutic approaches.展开更多
BACKGROUND Our mission is to cure hematopoietic malignancies through cell therapy.Time to transplant is a key challenge resulting in mortality of patients needing a transplant.Previous studies reported CD146+mesenchym...BACKGROUND Our mission is to cure hematopoietic malignancies through cell therapy.Time to transplant is a key challenge resulting in mortality of patients needing a transplant.Previous studies reported CD146+mesenchymal stem cells(MSCs)regulating hematopoiesis in bone marrow(BM).In 2013,the study reported the existence in the synovium of a MSC subset,co-expressing CD73 and CD39,with greater osteo-chondrogenic potency and ability to produce adenosine.This subset expressed CD146,known to be associated with pericytes.AIM To investigate the presence and characterization of the CD73+CD39+CD146+MSC subset in BM.Furthermore,we explored the existence of this subset in mobilized blood.METHODS BM cells were culture expanded up to passage 4.Flow cytometry was used to verify expression of CD73,CD39,and CD146 markers.Cell sorting was performed via BDFACS AriaTM Fusion.The subset was assessed for defined MSC characteristics and perivascular localization in BM sections.Peripheral blood derived MSCs were obtained through apheresis performed at Gift of Life under Institutional Review Board donor consent.RESULTS Our findings demonstrated that the combination of CD73,CD39,and CD146 enabled the identification and purification of a subset of MSCs from culture-expanded BM,up to passage 4.This subset exhibited a CD45-CD73+CD39+CD146+phenotype,along with self-renewal and multipotency abilities,and was located in perivascular areas of BM sections.Additionally,this subset was found in both single and dual-mobilized leukopaks.CONCLUSION The CD73+CD39+CD146+cell subset showed self-renewal and multipotency abilities and was located in perivascular areas of BM.Such cell subset was also reported in single and dual-mobilized leukopaks.展开更多
BACKGROUND Research has been increasingly conducted on the connection between mesenchymal stem cell(MSC)-conditioned medium(MSC-CM)and aging.However,most studies have focused on adipose-derived MSC-CM(ADMSC-CM),result...BACKGROUND Research has been increasingly conducted on the connection between mesenchymal stem cell(MSC)-conditioned medium(MSC-CM)and aging.However,most studies have focused on adipose-derived MSC-CM(ADMSC-CM),resulting in a research bias.We hypothesized that umbilical cord-derived MSCs,being younger than adipose-derived MSCs,would be more suitable for overcoming aging-related processes.AIM To assess the efficacy and safety of umbilical cord-derived MSC-CM(UCMSCCM)for preventing and treating skin aging.METHODS In vitro and in vivo studies were conducted to compare UCMSC-CM with ADMSC-CM,the most studied active aging-preventive conditioned medium to date.Additionally,the most effective delivery method of UCMSC-CM for aged skin was identified.RESULTS UCMSC-CM had a higher content of effective factors,stimulated higher proliferation of fibroblasts,and strongly inhibited melanin production in B16F1 cells.In aged mice,UCMSC-CM application increased skin thickness,the number of Ki-67-positive cells,and the area of collagen deposition.UCMSC-CM was more effective than ADMSC-CM in preventing and treating skin aging.Additionally,a safety evaluation of UCMSC-CM performed in various animal models indicated that it was safe even when used directly on the skin.CONCLUSION UCMSC-CM is effective and safe for preventing and treating skin aging.展开更多
BACKGROUND Mesenchymal stem cell(MSC)-based therapy may be a future treatment for myocardial infarction(MI).However,few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs(ADSCs)obtained from...BACKGROUND Mesenchymal stem cell(MSC)-based therapy may be a future treatment for myocardial infarction(MI).However,few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs(ADSCs)obtained from elderly patients in comparison to that of bone marrow-derived MSCs(BMSCs)from the same elderly patients.The metabolomics results revealed a significantly higher Larginine excretion from aged ADSCs vs BMSCs in hypoxic conditions.This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases.AIM To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy.METHODS Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed.Then,arginine succinate lyase(ASL)overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs.Subsequently,in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control,BMSCs,BMSCs ASL short hairpin RNA,BMSCs ASL overexpressed,and BMSC negative control on cocultured human umbilical vein endothelial cells.All sample sizes,which were determined to meet the statistical requirements and be greater than 3,were established on the basis of previously established literature standards.The protein levels of vascular endothelial growth factor(VEGF),basic fibroblast growth factor,etc.were detected.In vivo,the five types of cells were transplanted into the infarcted area of MI rat models,and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson’s staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area.RESULTS Metabolomic analysis showed that L-arginine was increased.Using ASL gene transfection,we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro,which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression,VEGF and basic fibroblast growth factor secretion,and inductive angiogenesis to levels comparable to donor-matched ADSCs.After the cell transplantation in vivo,the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells,enhanced vessel formation,reduced scar size,and improved cardiac function in the MI rat model.The therapeutic efficacy decreased by inhibiting L-arginine synthesis.CONCLUSION L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions.ADSCs have higher L-arginine secretion,which leads to better angiogenesis induction and cardiac protection.ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.展开更多
Heart failure(HF)is a complex syndrome characterized by the reduced capacity of the heart to adequately fill or eject blood.Currently,HF remains a leading cause of morbidity and mortality worldwide,imposing a substant...Heart failure(HF)is a complex syndrome characterized by the reduced capacity of the heart to adequately fill or eject blood.Currently,HF remains a leading cause of morbidity and mortality worldwide,imposing a substantial burden on global healthcare systems.Recent advancements have highlighted the therapeutic potential of mesenchymal stromal cells(MSCs)in managing HF.Notably,umbilical cord-derived MSCs(UC-MSCs)have demonstrated superior clinical potential compared to traditional bone marrow-derived MSCs;this is evident in their non-invasive collection process,higher proliferation efficacy,and lower immunogenicity and tumorigenicity,as substantiated by preclinical studies.Although the feasibility and safety of UC-MSCs have been tested in animal models,the application of UC-MSCs in HF treatment remains challenged by issues such as inaccurate targeted migration and low survival rates of UC-MSCs.Therefore,further research and clinical trials are imperative to advance the clinical application of UC-MSCs.展开更多
Pulmonary fibrosis significantly contributes to the pathogenesis of acute respiratory distress syndrome(ARDS),markedly increasing patient mortality.Despite the established anti-fibrotic effects of mesenchymal stem cel...Pulmonary fibrosis significantly contributes to the pathogenesis of acute respiratory distress syndrome(ARDS),markedly increasing patient mortality.Despite the established anti-fibrotic effects of mesenchymal stem cells(MSCs),numerous challenges hinder their clinical application.A recent study demon-strated that microvesicles(MVs)from MSCs(MSC-MVs)could attenuate ARDS-related pulmonary fibrosis and enhance lung function via hepatocyte growth factor mRNA transcription.This discovery presents a promising strategy for managing ARDS-associated pulmonary fibrosis.This article initially examines the safety and efficacy of MSCs from both basic science and clinical perspectives,subsequently exploring the potential and obstacles of employing MSC-MVs as a novel therapeutic approach.Additionally,it provides perspectives on future research into the application of MSC-MVs in ARDS-associated pulmonary fi-brosis.展开更多
The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells,which are essential for bone development and regeneration.However,the composition and potential use of bone m...The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells,which are essential for bone development and regeneration.However,the composition and potential use of bone marrow interstitial fluid have not been well explored.In this study,we report the role of neonatal bovine bone marrow interstitial fluid(NBIF)in enhancing the bone regeneration capacity of human bone marrow mesenchymal stem cells(hBMSCs).Unlike adult bovine bone marrow interstitial fluid(ABIF),NBIF-fed hBMSCs exhibit enhanced self-renewal and osteogenic potential and bone marrow homing ability,along with transcriptome changes as compared to hBMSCs cultured in standard fetal bovine serum(FBS)supplemented medium.Mass spectrometry analysis reveals that multiple secreted factors associated with tissue repair and bone development are enriched in NBIF compared to FBS and ABIF.The combined use of NBIF-enriched Nerve Growth Factor(NGF),Lactoferrin(LTF),and High Mobility Group Protein B1(HMGB1),together with Insulin-Like Growth Factor 1(IGF1)for culturing hBMSCs in the presence of FBS can enhance osteogenic potential and bone marrow homing ability,mimicking NBIF's effects.These findings highlight the role of interstitial fluid in the bone marrow microenvironment and its potential to optimize stem cell-based therapies.展开更多
“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health pro...“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.展开更多
Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to impr...Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.展开更多
Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,ha...Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,has garnered attention for cartilage repair in OA.While the iliac crest is the traditional site for bone marrow harvesting(BMH),associated morbidity has prompted the exploration of alternative sites such as the proximal tibia,distal femur,and proximal humerus.This paper reviews the impact of different harvesting sites on mesenchymal stem cell(MSC)yield,viability,and regenerative potential,emphasizing their relevance in knee OA treatment.The iliac crest consistently offers the highest MSC yield,but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity.The integration of harvesting techniques into existing knee surgeries,such as total knee arthroplasty,provides a less invasive approach while maintaining thera-peutic efficacy.However,variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes.Future directions include large-scale comparative studies,advanced characterization of MSCs,and the development of personalized harvesting strategies.Ultimately,the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA,enhancing their clinical utility and patient outcomes.展开更多
文摘Bone regeneration for non-load-bearing defects remains a significant clinical challenge requiring advanced biomaterials and cellular strategies.Adiposederived mesenchymal stem cells(AD-MSCs)have garnered significant interest in bone tissue engineering(BTE)because of their abundant availability,minimally invasive harvesting procedures,and robust differentiation potential into osteogenic lineages.Unlike bone marrow-derived mesenchymal stem cells,AD-MSCs can be easily obtained in large quantities,making them appealing alternatives for therapeutic applications.This review explores hydrogels containing polymers,such as chitosan,collagen,gelatin,and hyaluronic acid,and their composites,tailored for BTE,and emphasizes the importance of these hydrogels as scaffolds for the delivery of AD-MSCs.Various hydrogel fabrication techniques and biocompatibility assessments are discussed,along with innovative modifications to enhance osteogenesis.This review also briefly outlines AD-MSC isolation methods and advanced embedding techniques for precise cell placement,such as direct encapsulation and three-dimensional bioprinting.We discuss the mechanisms of bone regeneration in the AD-MSC-laden hydrogels,including osteoinduction,vascularization,and extracellular matrix remodeling.We also review the preclinical and clinical applications of AD-MSC-hydrogel systems,emphasizing their success and limitations.In this review,we provide a comprehensive overview of AD-MSC-based hydrogel systems to guide the development of effective therapies for bone regeneration.
基金supported by the Spanish Ministry of Health‐Plan Nacional sobre Drogas(2023‐I024)the the Ministry of Science,Innovation and Universities/State ResearchAgency/10.13039/501100011033(PID2023-146865OB-I00)+2 种基金Generalitat Valenciana(CIAICO/2021/203)the Primary Addiction Care Research Network(RD21/0009/0005)FEDER Funds,GVA.
文摘Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways.Chronic alcohol consumption leads to neuroinflammation,brain damage,and impaired cognition.Evidence indicates that females are more vulnerable to alcohol-induced damage than males.While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions,their potential to counteract alcohol-induced brain damage remains unclear.In this study,we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice.Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer(^(18)F-FDG)when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice.Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation,cognitive dysfunction,and the conditioned rewarding effects of cocaine.MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration.In addition,mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes(e.g.,Socs3,Tnf,Mtor,and Atf6)in the brains of ethanol-treated female mice.These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation,cognitive dysfunction,and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.
基金supported by the National Key R&D Program of China,Nos.2021YFA1101703/2021YFA1101700(to YD).
文摘Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.
基金supported by Zhejiang Provincial Natural Science Foundation of China(No.LQ23H290006)the National Natural Science Foundation of China(No.82204781)+2 种基金the Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province(No.2020E10021)Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents(No.ZWB-2020-18)Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project(No.2023ZR119).
文摘Mesenchymal stem cells(MSCs)are pluripotent stem cells isolated from human tissues.Due to their strong self-renewal capacity,pluripotency,and immunomodulatory properties,MSCs have garnered significant attention in cell therapy and tissue regeneration.However,cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation,making it crucial to develop interventions that delay or reverse the senescence process.From a traditional Chinese medicine perspective,senescence stems from spleen and stomach deficiency,kidney deficiency,and related factors;thus,medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy.Chinese medicine,characterized by low toxicity and multi-target,multi-functional properties,has become prominent in anti-senescence research.This paper examines the MSC senescence process by discussing its causes,characteristics,and mechanisms,then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence,facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.
基金supported by the National Natural Science Foundation of China,Nos.82271132(to YL),82101167(to BB)the Natural Science Foundation of Chongqing,Nos.CSTB2022NSCQ-MSX0020(to BB),cstc2019jcyj-msxmX0473(to FC).
文摘Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.
文摘BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention for its role in influencing their function,accessibility,and readiness for clinical use.AIM To identify the most suitable adipose source for MSC isolation and expansion for further applications.METHODS We isolated MSCs from solid adipose tissue and liposuction aspirates using the enzyme method.The MSCs were examined for their expansion using population doubling time,differentiation capacity using multilineage differentiation induction,surface markers using flow cytometry,and stability of chromosomes using the karyotyping method.Growth factors and cytokines in MSC-conditioned media were analyzed using the Luminex assay.RESULTS MSCs were isolated from solid adipose tissue and lipoaspirates and expanded from passage 0 to passage 2.All adipose-derived MSCs(AD-MSCs)exhibited the typical elongated,spindle-shaped morphology and comparable proliferation rate.They expressed positive surface markers(cluster of differentiation 73[CD73]:>97%,CD90:>98%,and CD105:>95%),and negative markers(<1%).All MSCs expressed similar levels of stemness genes(octamer-binding transcription factor 4,SRY-box 2,Krüppel-like factor,and MYC),colonyforming,and trilineage differentiation potential.Karyotyping analysis revealed normal chromosomal patterns in all samples,except one sample exhibiting a polymorphism(1qh+).Furthermore,the growth factors and cytokines of hepatocyte growth factor,vascular endothelial growth factor A,interleukin 6(IL-6),and IL-8 were detected in all AD-MSC conditioned media;but fibroblast growth factor-2 and keratinocyte growth factor were selectively expressed in conditioned media from solid or lipoaspirate AD-MSCs,respectively.CONCLUSION These findings indicate that AD-MSCs from both adipose sources possess all of the characteristic features of MSCs with source-specific secretome differences,which are suitable for further expansion and various clinical applications.
基金supported by the Medicine-Engineering Interdisciplinary Project of Sun Yat-sen Memorial Hospital,China,No.YXYGRH202203(to YW)Key-Area Research and Development Program of Guangdong Province,China,No.2023B1111050003(to HC)Guangzhou Science and Technology Talent Project of China,No.201909020006(to HC).
文摘Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.
基金supported by the National Key R&D Program of China,Nos.2017YFA0104302(to NG and XM)and 2017YFA0104304(to BW and ZZ)
文摘Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in humans remain unclear,including cell viability,distribution,migration,and fate.Conventional cell tracing methods cannot be used in the clinic.The use of superparamagnetic iron oxide nanoparticles as contrast agents allows for the observation of transplanted cells using magnetic resonance imaging.In 2016,the National Medical Products Administration of China approved a new superparamagnetic iron oxide nanoparticle,Ruicun,for use as a contrast agent in clinical trials.In the present study,an acute hemi-transection spinal cord injury model was established in beagle dogs.The injury was then treated by transplantation of Ruicun-labeled mesenchymal stromal cells.The results indicated that Ruicunlabeled mesenchymal stromal cells repaired damaged spinal cord fibers and partially restored neurological function in animals with acute spinal cord injury.T2*-weighted imaging revealed low signal areas on both sides of the injured spinal cord.The results of quantitative susceptibility mapping with ultrashort echo time sequences indicated that Ruicun-labeled mesenchymal stromal cells persisted stably within the injured spinal cord for over 4 weeks.These findings suggest that magnetic resonance imaging has the potential to effectively track the migration of Ruicun-labeled mesenchymal stromal cells and assess their ability to repair spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.32171356(to YW)Self-Support Research Projects of Shihezi University,No.ZZZC2021105(to WJ)+1 种基金Capital Medical University Natural Science Cultivation Fund,No.PYZ23044(to FQM)Beijing Municipal Natural Science Foundation,No.7244410(to JHD)。
文摘Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
基金Supported by Natural Science Foundation of Zhejiang Province,No.LY23H050005Zhejiang Medical Technology Project,No.2020KY439,No.2022RC009,No.2024KY645,and No.2024KY697.
文摘Lupus nephritis(LN)is one of the most common and serious complications of systemic lupus erythematosus,which can lead to end-stage renal disease,and is an important cause of death in patients with systemic lupus erythematosus.Treatment options include glucocorticoids,immunosuppressive agents and the addition of biologics.Recently,the therapeutic role of mesenchymal stem cells(MSCs)in LN has received extensive attention worldwide.MSCs can suppress autoimmunity,alleviate proteinuria and restore renal function by modulating the functions of various immune cells and reducing the secretion of inflammatory cytokines.Several clinical trials have investigated MSC treatment in LN with promising but sometimes inconsistent outcomes.This review summarizes the sources of MSCs and mechanisms in immunoregulation.Furthermore,it examines clinical trials evaluating the efficacy,safety,and limitations of MSC therapy in LN.By highlighting advances and ongoing challenges,this review underscores the potential of MSCs for LN treatment.More large-scale randomized controlled trials are needed to support the effectiveness of this therapy and pave the way for personalized and combinatorial therapeutic approaches.
文摘BACKGROUND Our mission is to cure hematopoietic malignancies through cell therapy.Time to transplant is a key challenge resulting in mortality of patients needing a transplant.Previous studies reported CD146+mesenchymal stem cells(MSCs)regulating hematopoiesis in bone marrow(BM).In 2013,the study reported the existence in the synovium of a MSC subset,co-expressing CD73 and CD39,with greater osteo-chondrogenic potency and ability to produce adenosine.This subset expressed CD146,known to be associated with pericytes.AIM To investigate the presence and characterization of the CD73+CD39+CD146+MSC subset in BM.Furthermore,we explored the existence of this subset in mobilized blood.METHODS BM cells were culture expanded up to passage 4.Flow cytometry was used to verify expression of CD73,CD39,and CD146 markers.Cell sorting was performed via BDFACS AriaTM Fusion.The subset was assessed for defined MSC characteristics and perivascular localization in BM sections.Peripheral blood derived MSCs were obtained through apheresis performed at Gift of Life under Institutional Review Board donor consent.RESULTS Our findings demonstrated that the combination of CD73,CD39,and CD146 enabled the identification and purification of a subset of MSCs from culture-expanded BM,up to passage 4.This subset exhibited a CD45-CD73+CD39+CD146+phenotype,along with self-renewal and multipotency abilities,and was located in perivascular areas of BM sections.Additionally,this subset was found in both single and dual-mobilized leukopaks.CONCLUSION The CD73+CD39+CD146+cell subset showed self-renewal and multipotency abilities and was located in perivascular areas of BM.Such cell subset was also reported in single and dual-mobilized leukopaks.
文摘BACKGROUND Research has been increasingly conducted on the connection between mesenchymal stem cell(MSC)-conditioned medium(MSC-CM)and aging.However,most studies have focused on adipose-derived MSC-CM(ADMSC-CM),resulting in a research bias.We hypothesized that umbilical cord-derived MSCs,being younger than adipose-derived MSCs,would be more suitable for overcoming aging-related processes.AIM To assess the efficacy and safety of umbilical cord-derived MSC-CM(UCMSCCM)for preventing and treating skin aging.METHODS In vitro and in vivo studies were conducted to compare UCMSC-CM with ADMSC-CM,the most studied active aging-preventive conditioned medium to date.Additionally,the most effective delivery method of UCMSC-CM for aged skin was identified.RESULTS UCMSC-CM had a higher content of effective factors,stimulated higher proliferation of fibroblasts,and strongly inhibited melanin production in B16F1 cells.In aged mice,UCMSC-CM application increased skin thickness,the number of Ki-67-positive cells,and the area of collagen deposition.UCMSC-CM was more effective than ADMSC-CM in preventing and treating skin aging.Additionally,a safety evaluation of UCMSC-CM performed in various animal models indicated that it was safe even when used directly on the skin.CONCLUSION UCMSC-CM is effective and safe for preventing and treating skin aging.
基金Supported by the National Natural Science Foundation of China,No.82472147the Key Research and Development Program of Heilongjiang Province of China,No.2023ZX06C04the Open Fund of Key Laboratory of Hepatosplenic Surgery,Ministry of Education,Harbin,China,No.GPKF202402.
文摘BACKGROUND Mesenchymal stem cell(MSC)-based therapy may be a future treatment for myocardial infarction(MI).However,few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs(ADSCs)obtained from elderly patients in comparison to that of bone marrow-derived MSCs(BMSCs)from the same elderly patients.The metabolomics results revealed a significantly higher Larginine excretion from aged ADSCs vs BMSCs in hypoxic conditions.This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases.AIM To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy.METHODS Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed.Then,arginine succinate lyase(ASL)overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs.Subsequently,in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control,BMSCs,BMSCs ASL short hairpin RNA,BMSCs ASL overexpressed,and BMSC negative control on cocultured human umbilical vein endothelial cells.All sample sizes,which were determined to meet the statistical requirements and be greater than 3,were established on the basis of previously established literature standards.The protein levels of vascular endothelial growth factor(VEGF),basic fibroblast growth factor,etc.were detected.In vivo,the five types of cells were transplanted into the infarcted area of MI rat models,and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson’s staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area.RESULTS Metabolomic analysis showed that L-arginine was increased.Using ASL gene transfection,we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro,which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression,VEGF and basic fibroblast growth factor secretion,and inductive angiogenesis to levels comparable to donor-matched ADSCs.After the cell transplantation in vivo,the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells,enhanced vessel formation,reduced scar size,and improved cardiac function in the MI rat model.The therapeutic efficacy decreased by inhibiting L-arginine synthesis.CONCLUSION L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions.ADSCs have higher L-arginine secretion,which leads to better angiogenesis induction and cardiac protection.ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.
文摘Heart failure(HF)is a complex syndrome characterized by the reduced capacity of the heart to adequately fill or eject blood.Currently,HF remains a leading cause of morbidity and mortality worldwide,imposing a substantial burden on global healthcare systems.Recent advancements have highlighted the therapeutic potential of mesenchymal stromal cells(MSCs)in managing HF.Notably,umbilical cord-derived MSCs(UC-MSCs)have demonstrated superior clinical potential compared to traditional bone marrow-derived MSCs;this is evident in their non-invasive collection process,higher proliferation efficacy,and lower immunogenicity and tumorigenicity,as substantiated by preclinical studies.Although the feasibility and safety of UC-MSCs have been tested in animal models,the application of UC-MSCs in HF treatment remains challenged by issues such as inaccurate targeted migration and low survival rates of UC-MSCs.Therefore,further research and clinical trials are imperative to advance the clinical application of UC-MSCs.
文摘Pulmonary fibrosis significantly contributes to the pathogenesis of acute respiratory distress syndrome(ARDS),markedly increasing patient mortality.Despite the established anti-fibrotic effects of mesenchymal stem cells(MSCs),numerous challenges hinder their clinical application.A recent study demon-strated that microvesicles(MVs)from MSCs(MSC-MVs)could attenuate ARDS-related pulmonary fibrosis and enhance lung function via hepatocyte growth factor mRNA transcription.This discovery presents a promising strategy for managing ARDS-associated pulmonary fibrosis.This article initially examines the safety and efficacy of MSCs from both basic science and clinical perspectives,subsequently exploring the potential and obstacles of employing MSC-MVs as a novel therapeutic approach.Additionally,it provides perspectives on future research into the application of MSC-MVs in ARDS-associated pulmonary fi-brosis.
基金financially supported by the Guangzhou National Laboratory(grant#GZNL2025C02022,A.M.#QNPG2317,J.Z.)partially by the National Natural Science Foundation of China(31988101)。
文摘The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells,which are essential for bone development and regeneration.However,the composition and potential use of bone marrow interstitial fluid have not been well explored.In this study,we report the role of neonatal bovine bone marrow interstitial fluid(NBIF)in enhancing the bone regeneration capacity of human bone marrow mesenchymal stem cells(hBMSCs).Unlike adult bovine bone marrow interstitial fluid(ABIF),NBIF-fed hBMSCs exhibit enhanced self-renewal and osteogenic potential and bone marrow homing ability,along with transcriptome changes as compared to hBMSCs cultured in standard fetal bovine serum(FBS)supplemented medium.Mass spectrometry analysis reveals that multiple secreted factors associated with tissue repair and bone development are enriched in NBIF compared to FBS and ABIF.The combined use of NBIF-enriched Nerve Growth Factor(NGF),Lactoferrin(LTF),and High Mobility Group Protein B1(HMGB1),together with Insulin-Like Growth Factor 1(IGF1)for culturing hBMSCs in the presence of FBS can enhance osteogenic potential and bone marrow homing ability,mimicking NBIF's effects.These findings highlight the role of interstitial fluid in the bone marrow microenvironment and its potential to optimize stem cell-based therapies.
基金supported by the Key Research and Development Project of Hubei Province of China,2022BCA028(to HC)。
文摘“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.
基金supported by the Natural Science Fund of Fujian Province,No.2020J011058(to JK)the Project of Fujian Provincial Hospital for High-level Hospital Construction,No.2020HSJJ12(to JK)+1 种基金the Fujian Provincial Finance Department Special Fund,No.(2021)848(to FC)the Fujian Provincial Major Scientific and Technological Special Projects on Health,No.2022ZD01008(to FC).
文摘Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.
文摘Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,has garnered attention for cartilage repair in OA.While the iliac crest is the traditional site for bone marrow harvesting(BMH),associated morbidity has prompted the exploration of alternative sites such as the proximal tibia,distal femur,and proximal humerus.This paper reviews the impact of different harvesting sites on mesenchymal stem cell(MSC)yield,viability,and regenerative potential,emphasizing their relevance in knee OA treatment.The iliac crest consistently offers the highest MSC yield,but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity.The integration of harvesting techniques into existing knee surgeries,such as total knee arthroplasty,provides a less invasive approach while maintaining thera-peutic efficacy.However,variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes.Future directions include large-scale comparative studies,advanced characterization of MSCs,and the development of personalized harvesting strategies.Ultimately,the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA,enhancing their clinical utility and patient outcomes.
