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
“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
Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with ...Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.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
BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.Th...BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.There are studies suggesting that stem cell therapy may be effective in the treatment of ASD.AIM To evolve the landscape of ASD treatment,focusing on the potential benefits and safety of stem cell transplantation.METHODS A detailed case report is presented,displaying the positive outcomes observed in a child who underwent intrathecal and intravenous Wharton’s jelly-derived mesenchymal stem cells(WJ-MSCs)transplantation combined with neurorehabilitation.RESULTS The study demonstrates a significant improvement in the child’s functional outcomes(Childhood Autism Rating Scale,Denver 2 Developmental Screening Test),especially in language and gross motor skills.No serious side effects were encountered during the 2-year follow-up.CONCLUSION The findings support the safety and effectiveness of WJ-MSC transplantation in managing ASD.展开更多
Mesenchymalstemcells(MSCs)areidealcandidatesfortreatingmanycardiovasculardiseases.MSCscanmodify the internal cardiac microenvironment to facilitate their immunomodulatory and differentiation abilities,which are essent...Mesenchymalstemcells(MSCs)areidealcandidatesfortreatingmanycardiovasculardiseases.MSCscanmodify the internal cardiac microenvironment to facilitate their immunomodulatory and differentiation abilities,which are essential to restore heart function.MSCs can be easily isolated from different sources,including bone marrow,adipose tissues,umbilical cord,and dental pulp.MSCs from various sources differ in their regenerative and therapeutic abilities for cardiovascular disorders.In this review,we will summarize the therapeutic potential of each MSC source for heart diseases and highlight the possible molecular mechanisms of each source to restore cardiac function.展开更多
BACKGROUND As living biodrugs,mesenchymal stem cells(MSCs)have progressed to phase 3 clinical trials for cardiovascular applications.However,their limited immediate availability hampers their routine clinical use.AIM ...BACKGROUND As living biodrugs,mesenchymal stem cells(MSCs)have progressed to phase 3 clinical trials for cardiovascular applications.However,their limited immediate availability hampers their routine clinical use.AIM To validate our hypothesis that cryopreserved MSCs(CryoMSCs)are as safe and effective as freshly cultured MSC counterparts but carry logistical advantages.METHODS Four databases were systematically reviewed for relevant randomized controlled trials(RCTs)evaluating the safety and efficacy of CryoMSCs from various tissue sources in treating patients with heart disease.A subgroup analysis was performed based on MSC source and post-thaw cell viability to determine treatment effects across different CryoMSCs sources and viability status.Weighted mean differences(WMDs)and odds ratios were calculated to measure changes in the estimated treatment effects.All statistical analyses were performed using RevMan version 5.4.1 software.RESULTS Seven RCTs(285 patients)met the eligibility criteria for inclusion in the metaanalysis.During short-term follow-up,^(Cryo)MSCs demonstrated a significant 2.11%improvement in left ventricular ejection fraction(LVEF)[WMD(95%CI)=2.11(0.66-3.56),P=0.004,I2=1%],with umbilical cord-derived MSCs being the most effective cell type.However,the significant effect on LVEF was not sustained over the 12 months of follow-up.Subgroup analysis demonstrated a substantial 3.44%improvement in LVEF[WMD(95%CI)=3.44(1.46-5.43),P=0.0007,I2=0%]when using MSCs with post-thaw viability exceeding 80%.There was no statistically significant difference in the frequency of major cardiac adverse events observed in rehospitalization or mortality in patients treated with ^(Cryo)MSCs vs the control group.CONCLUSION ^(Cryo)MSCs are a promising option for heart failure patients,particularly considering the current treatment options for cardiovascular diseases.Our data suggest that ^(Cryo)MSCs could be a viable alternative or complementary treatment to the current options,potentially improving patient outcomes.展开更多
BACKGROUND Acute lung injury(ALI)is a fatal and heterogeneous disease.While bone marrow mesenchymal stem cells(BMSCs)have shown promise in ALI repair,their efficacy is compromised by a high apoptotic percentage.Prelim...BACKGROUND Acute lung injury(ALI)is a fatal and heterogeneous disease.While bone marrow mesenchymal stem cells(BMSCs)have shown promise in ALI repair,their efficacy is compromised by a high apoptotic percentage.Preliminary findings have indicated that long noncoding RNA(lncRNA)-ENST expression is markedly downregulated in MSCs under ischemic and hypoxic conditions,establishing a rationale for in vitro exploration.AIM To elucidate the role of lncRNA-ENST00000517482(lncRNA-ENST)in modulating MSC apoptosis.METHODS Founded on ALI in BEAS-2B cells with lipopolysaccharide,this study employed a transwell co-culture system to study BMSC tropism.BMSCs were genetically modified to overexpress or knockdown lncRNA-ENST.After analyzing the effects on autophagy,apoptosis and cell viability,the lncRNA-ENST/miR-539/c-MYC interaction was confirmed by dual-luciferase assays.RESULTS These findings have revealed a strong correlation between lncRNA-ENST levels and the apoptotic and autophagic status of BMSCs.On the one hand,the overexpression of lncRNA-ENST,as determined by Cell Counting Kit-8 assays,increased the expression of autophagy markers LC3B,ATG7,and ATG5.On the other hand,it reduced apoptosis and boosted BMSC viability.In co-cultures with BEAS-2B cells,lncRNA-ENST overexpression also improved cell vitality.Additionally,by downregulating miR-539 and upregulating c-MYC,lncRNA-ENST was found to influence mitochondrial membrane potential,enhance BMSC autophagy,mitigate apoptosis and lower the secretion of proinflammatory cytokines interleukin-6 and interleukin-1β.Collectively,within the in vitro framework,these results have highlighted the therapeutic potential of BMSCs in ALI and the pivotal regulatory role of lncRNA-ENST in miR-539 and apoptosis in lipopolysaccharide-stimulated BEAS-2B cells.CONCLUSION Our in vitro results show that enhanced lncRNA ENST expression can promote BMSC proliferation and viability by modulating the miR-539/c-MYC axis,reduce apoptosis and induce autophagy,which has suggested its therapeutic potential in the treatment of ALI.展开更多
Publications of Soufan et al and Kristjánsson et al in the World Journal of Orthopedics on mesenchymal stem cell(MSC)therapy for osteoarthritis(OA)represent a significant exploration of regenerative medicine’s p...Publications of Soufan et al and Kristjánsson et al in the World Journal of Orthopedics on mesenchymal stem cell(MSC)therapy for osteoarthritis(OA)represent a significant exploration of regenerative medicine’s potential in OA treatment.In their research,it is highlighted that MSCs can alleviate OA symptoms and even regenerate cartilage,potentially reversing the disease.They also compared the efficacy of three MSC subtypes,emphasizing the therapeutic advantages of adipose-derived MSCs.MSC injections,a novel and less invasive alternative to traditional treatments such as chondrocyte transplantation or arthroplasty,have a low cost,low risks,and favorable outcomes,presenting a promising approach for OA patients.Additionally,we stressed that the efficacy evaluation criteria,heterogeneity,safety,and other factors must be carefully considered to further advance the clinical translation of MSC therapy for OA.展开更多
BACKGROUND Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)can traverse the blood-brain barrier due to their small size.This characteristic makes them a research hotspot for the treatment of Parkinson’s ...BACKGROUND Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)can traverse the blood-brain barrier due to their small size.This characteristic makes them a research hotspot for the treatment of Parkinson’s disease(PD)and is expected to be a potentially revolutionary strategy for treating PD.Despite this,no summary of clinical trial results has been reported.AIM To assess the efficacy and durability of MSC-EVs in treating PD.METHODS Systematic searches were conducted in four electronic databases until June 2024 to collect studies on the use of MSC-EVs for this purpose.Thirteen relevant randomized controlled trials,encompassing 16 experiments,were selected for inclusion.RESULTS Behavioral assessments,including the rotarod and apomorphine turning behavior tests,indicated improvements in motor coordination(P<0.00001);the Pole test and the Wire-hang test showed enhanced limb motor agility and synchronization(P=0.003 and P<0.00001,respectively).Histopathologically,there was a reduction in inflammatory markers such as tumor necrosis factor-αand interleukin-6(P=0.03 and P=0.01,respectively)and an increase in tyrosine hydroxylase-positive cells in the lesion areas(P<0.00001).CONCLUSION MSC-EV therapy for PD is a gradual process,with significant improvements observable more than 2 weeks after administration and lasting at least 8 weeks.This study is the first to demonstrate the efficacy and durability of MSC-EV treatment in PD.展开更多
In this editorial,we comment on the recent article by Xiao et al,focusing on their investigation into whether the therapeutic efficacy of serum-free human umbilical cord mesenchymal stem cells(MSCs)differs from that o...In this editorial,we comment on the recent article by Xiao et al,focusing on their investigation into whether the therapeutic efficacy of serum-free human umbilical cord mesenchymal stem cells(MSCs)differs from that of serum-containing human umbilical cord MSCs in a mouse model of knee osteoarthritis(OA).The incidence of OA has significantly increased in recent years,primarily owing to sports-related injuries or degenerative diseases.However,the regenerative capacity of articular cartilage remains limited,necessitating artificial joint replacement for patients with advanced OA to enhance the quality of life.MSCs have been widely used in the clinical treatment of OA owing to their multidirectional differentiation potential and immunomodulatory effects.The focus of this paper lies in elucidating the mechanism underlying MSC transplantation for the treatment of knee OA,while also addressing the challenges encountered in MSC therapy and outlining future directions.展开更多
This article discusses the study by Xiao et al,which investigated the therapeutic efficacy of serum-free cultured human umbilical cord mesenchymal stem cells(NhUCMSCs)in a mouse model of knee osteoarthritis.The result...This article discusses the study by Xiao et al,which investigated the therapeutic efficacy of serum-free cultured human umbilical cord mesenchymal stem cells(NhUCMSCs)in a mouse model of knee osteoarthritis.The results showed that NhUCMSCs alleviated osteoarthritis-related cartilage damage and inflammation comparably to both serum-cultured hUCMSCs and hyaluronic acid.While these findings broaden the potential clinical utility of N-hUCMSCs by circumventing certain drawbacks of serum-based cultures,the equivalence in efficacy raises important questions.First,how do N-hUCMSCs differ phenotypically from serum-cultured hUCMSCs,particularly in terms of proliferation rate,replicative capacity,and senescence profile?Second,what advantages might N-hUCMSCs offer over hyaluronic acid-a well-established therapy-beyond avoiding xenogeneic components and ethical concerns?Future research should focus on longterm phenotypic stability,sustained functional benefits,safety profiles,and mechanistic insights to ascertain whether N-hUCMSCs can surpass current standards of care.展开更多
Exosomes(Exos)are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication.They play a pivotal role in the pathogenesis and progression of various diseases and offer promi...Exosomes(Exos)are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication.They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions.Exos derived from mesenchymal stem cells(MSCs)have significant immunomodulatory properties.They effectively regulate immune responses by modulating both innate and adaptive immunity.These Exos can inhibit excessive inflammatory responses and promote tissue repair.Moreover,they participate in antigen presentation,which is essential for activating immune responses.The cargo of these Exos,including ligands,proteins,and microRNAs,can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response.By inhibiting lymphocyte proliferation,acting on macrophages,and increasing the population of regulatory T cells,these Exos contribute to maintaining immune and metabolic homeostasis.Furthermore,they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells,which holds potential for immunotherapy applications.Given the immense therapeutic potential of MSC-derived Exos,this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control,tumor suppression,and autoimmune disease management.This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos,offering theoretical references for their future clinical utilization as cell-free drug preparations.展开更多
Acute kidney injury(AKI)is a clinical syndrome characterized by a rapid deterioration in kidney function and has a significant impact on patient health and survival.Mesenchymal stem cells(MSCs)have the potential to en...Acute kidney injury(AKI)is a clinical syndrome characterized by a rapid deterioration in kidney function and has a significant impact on patient health and survival.Mesenchymal stem cells(MSCs)have the potential to enhance renal function by suppressing the expression of cell cycle inhibitors and reducing the expression of senescence markers and microRNAs via paracrine and endocrine mechanisms.MSC-derived exosomes can alleviate AKI symptoms by regulating DNA damage,apoptosis,and other related signaling pathways through the delivery of proteins,microRNAs,long-chain noncoding RNAs,and circular RNAs.This technique is both safe and effective.MSC-derived exosomes may have great application prospects in the treatment of AKI.Understanding the underlying mechanisms will foster the development of new and promising therapeutic strategies against AKI.This review focused on recent advancements in the role of MSCs in AKI repair as well as the mechanisms underlying the role of MSCs and their secreted exosomes.It is anticipated that novel and profound insights into the functionality of MSCs and their derived exosomes will emerge.展开更多
BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage.However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells(BMSCs),is...BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage.However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells(BMSCs),is less reported.BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis;however,the impairment caused by sepsis remains unknown.AIM To investigate the effects of sepsis on BMSCs and the underlying mechanisms.METHODS BMSCs were obtained from healthy donors and patients with sepsis.We compared the self-renewal capacity,differentiation potential,and hematopoietic supportive ability in vitro.Senescence of septic BMSCs was assessed usingβ-galactosidase staining,senescence-associated secretory phenotype,intracellular reactive oxygen species levels,and the expression of P16 and P21.Finally,the changes in septic BMSCs after nicotinamide adenine dinucleotide(NAD)treatment were evaluated.RESULTS Septic BMSCs showed decreased proliferation and self-renewal,bias towards adipogenic differentiation,and weakened osteogenic differentiation.Additionally,hematopoietic supportive capacity declines in sepsis.The levels of aging markers were significantly higher in the septic BMSCs.After NAD treatment,the proliferation capacity of septic BMSCs showed a recovery trend,with increased osteogenic and hematopoietic supportive capacities.Sepsis resulted in decreased expression of sirtuin 3(SIRT3)in BMSCs,whereas NAD treatment restored SIRT3 expression,enhanced superoxide dismutase enzyme activity,reduced intracellular reactive oxygen species levels,maintained mitochondrial stability and function,and ultimately rejuvenated septic BMSCs.CONCLUSION Sepsis accelerates the aging of BMSCs,as evidenced by a decline in self-renewal and osteogenic capabilities,as well as weakened hematopoietic support functions.These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway.展开更多
BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA ...BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA treatments,their use is limited by the condition itself,and understanding of the underlying mechanisms of OA is lacking.AIM To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.METHODS Sodium iodoacetate was injected into rat articulations to construct an animal model of OA.Interleukin(IL)-1βwas used to induce human chondrocytes(CHON-001)to construct an OA chondrocyte model.Exosomes in hUC-MSCs were isolated using Ribo™Exosome Isolation Reagent.Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins,and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay,terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho-sphate-nick end labelling staining and hematoxylin and eosin staining.RESULTS hUC-MSC-derived exosomes(hUC-MSC-Exos)inhibited the expression of IL-1β-induced inflammatory cytokines,namely,IL-6,IL-8 and tumor necrosis factor-α.hUC-MSC-Exos also improved the viability but inhibited the apoptosis of CHON-001 cells,improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo.Mechanistically,hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p,thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway,alleviating IL-1β-induced chondrocyte inflammation and apoptosis,and ultimately improving the development of OA.CONCLUSION hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway.The present findings suggest that miR-199a-3p delivery by hUC-MSCExos may be a novel strategy for the treatment of OA.展开更多
BACKGROUND Mesenchymal stem cells,found in various tissues,possess significant healing and immunomodulatory properties,influencing macrophage polarization,which is essential for wound repair.However,chronic wounds pre...BACKGROUND Mesenchymal stem cells,found in various tissues,possess significant healing and immunomodulatory properties,influencing macrophage polarization,which is essential for wound repair.However,chronic wounds present significant therapeutic challenges,requiring novel strategies to improve healing outcomes.AIM To investigate the potential of fetal dermal mesenchymal stem cells(FDMSCs)in enhancing wound healing through modulation of macrophage polarization,specifically by promoting the M2 phenotype to address inflammatory responses in chronic wounds.METHODS FDMSCs were isolated from BalB/C mice and co-cultured with RAW264.7 macrophages to assess their effects on macrophage polarization.Flow cytometry,quantitative reverse transcriptase polymerase chain reaction,and histological analyses were employed to evaluate shifts in macrophage phenotype and wound healing in a mouse model.Statistical analysis was performed using GraphPad Prism.RESULTS FDMSCs induced macrophage polarization from the M1 to M2 phenotype,as demonstrated by a reduction in proinflammatory markers(inducible nitric oxide synthase,interleukin-6)and an increase in anti-inflammatory markers[mannose receptor(CD206),arginase-1]in co-cultured RAW264.7 macrophages.These shifts were confirmed by flow cytometry.In an acute skin wound model,FDMSC-treated mice exhibited faster wound healing,enhanced collagen deposition,and improved vascular regeneration compared to controls.Significantly higher expression of arginase-1 further indicated an enriched M2 macrophage environment.CONCLUSION FDMSCs effectively modulate macrophage polarization from M1 to M2,reduce inflammation,and enhance tissue repair,demonstrating their potential as an immunomodulatory strategy in wound healing.These findings highlight the promising therapeutic application of FDMSCs in managing chronic wounds.展开更多
BACKGROUND Mesenchymal stem cells(MSCs)and their secretome have significant potential in promoting hair follicle development.However,the effects of MSC therapy have been reported to vary due to their heterogeneous cha...BACKGROUND Mesenchymal stem cells(MSCs)and their secretome have significant potential in promoting hair follicle development.However,the effects of MSC therapy have been reported to vary due to their heterogeneous characteristics.Different sources of MSCs or culture systems may cause heterogeneity of exosomes.AIM To define the potential of human adipose-derived MSC exosomes(hADSC-Exos)and human umbilical cord-derived MSC exosomes(hUCMSC-Exos)for improving dermal papillary cell proliferation in androgenetic alopecia.METHODS We conducted liquid chromatography-mass spectrometry proteomic analysis of hADSC-Exos and hUCMSC-Exos.Liquid chromatography-mass spectrometry suggested that hADSC-Exos were related to metabolism and immunity.Additionally,the hADSC-Exo proteins regulated the cell cycle and other 9 functional groups.RESULTS We verified that hADSC-Exos inhibited glycogen synthase kinase-3βexpression by activating the Wnt/β-catenin signaling pathway via cell division cycle protein 42,and enhanced dermal papillary cell proliferation and migration.Excess dihydrotestosterone caused androgenetic alopecia by shortening the hair follicle growth phase,but hADSC-Exos reversed these effects.CONCLUSION This study indicated that hair development is influenced by hADSC-Exo-mediated cell-to-cell communication via the Wnt/β-catenin pathway.展开更多
The potential of induced pluripotent stem cells(iPSCs)for modeling and treating metabolic associated fatty liver disease(MAFLD)and metabolic associated steatohepatitis(MASH)is emerging.MAFLD is a growing global health...The potential of induced pluripotent stem cells(iPSCs)for modeling and treating metabolic associated fatty liver disease(MAFLD)and metabolic associated steatohepatitis(MASH)is emerging.MAFLD is a growing global health concern,currently with limited treatment options.While primary mesenchymal stem cells hold promise,iPSCs offer a versatile alternative due to their ability to differentiate into various cell types,including iPSC-derived mesenchymal stem cells.However,challenges remain,including optimizing differentiation protocols,ensuring cell safety,and addressing potential tumorigenicity risks.In addition,iPSCs offer the possibility to generate complex cellular models,including three-dimensional organoid models,which are closer representations of the human disease than animal models.Those models would also be valuable for drug discovery and personalized medicine approaches.Overall,iPSCs and their derivatives offer new perspectives for advancing MAFLD/MASH research and developing novel therapeutic strategies.Further research is needed to overcome current limitations and translate this potential into effective clinical applications.展开更多
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.
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.
基金supported by grants from the Spanish Ministry of Health-PNSD(2019-I039 and 2023-I024)(to MP)FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación PID2021-1243590B-I100(to VMM)+2 种基金GVA(CIAICO/2021/203)(to MP)the Primary Addiction Care Research Network(RD21/0009/0005)(to MP)a predoctoral fellowship from the Generalitat Valenciana(ACIF/2021/338)(to CPC).
文摘Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.
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.
文摘BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.There are studies suggesting that stem cell therapy may be effective in the treatment of ASD.AIM To evolve the landscape of ASD treatment,focusing on the potential benefits and safety of stem cell transplantation.METHODS A detailed case report is presented,displaying the positive outcomes observed in a child who underwent intrathecal and intravenous Wharton’s jelly-derived mesenchymal stem cells(WJ-MSCs)transplantation combined with neurorehabilitation.RESULTS The study demonstrates a significant improvement in the child’s functional outcomes(Childhood Autism Rating Scale,Denver 2 Developmental Screening Test),especially in language and gross motor skills.No serious side effects were encountered during the 2-year follow-up.CONCLUSION The findings support the safety and effectiveness of WJ-MSC transplantation in managing ASD.
文摘Mesenchymalstemcells(MSCs)areidealcandidatesfortreatingmanycardiovasculardiseases.MSCscanmodify the internal cardiac microenvironment to facilitate their immunomodulatory and differentiation abilities,which are essential to restore heart function.MSCs can be easily isolated from different sources,including bone marrow,adipose tissues,umbilical cord,and dental pulp.MSCs from various sources differ in their regenerative and therapeutic abilities for cardiovascular disorders.In this review,we will summarize the therapeutic potential of each MSC source for heart diseases and highlight the possible molecular mechanisms of each source to restore cardiac function.
文摘BACKGROUND As living biodrugs,mesenchymal stem cells(MSCs)have progressed to phase 3 clinical trials for cardiovascular applications.However,their limited immediate availability hampers their routine clinical use.AIM To validate our hypothesis that cryopreserved MSCs(CryoMSCs)are as safe and effective as freshly cultured MSC counterparts but carry logistical advantages.METHODS Four databases were systematically reviewed for relevant randomized controlled trials(RCTs)evaluating the safety and efficacy of CryoMSCs from various tissue sources in treating patients with heart disease.A subgroup analysis was performed based on MSC source and post-thaw cell viability to determine treatment effects across different CryoMSCs sources and viability status.Weighted mean differences(WMDs)and odds ratios were calculated to measure changes in the estimated treatment effects.All statistical analyses were performed using RevMan version 5.4.1 software.RESULTS Seven RCTs(285 patients)met the eligibility criteria for inclusion in the metaanalysis.During short-term follow-up,^(Cryo)MSCs demonstrated a significant 2.11%improvement in left ventricular ejection fraction(LVEF)[WMD(95%CI)=2.11(0.66-3.56),P=0.004,I2=1%],with umbilical cord-derived MSCs being the most effective cell type.However,the significant effect on LVEF was not sustained over the 12 months of follow-up.Subgroup analysis demonstrated a substantial 3.44%improvement in LVEF[WMD(95%CI)=3.44(1.46-5.43),P=0.0007,I2=0%]when using MSCs with post-thaw viability exceeding 80%.There was no statistically significant difference in the frequency of major cardiac adverse events observed in rehospitalization or mortality in patients treated with ^(Cryo)MSCs vs the control group.CONCLUSION ^(Cryo)MSCs are a promising option for heart failure patients,particularly considering the current treatment options for cardiovascular diseases.Our data suggest that ^(Cryo)MSCs could be a viable alternative or complementary treatment to the current options,potentially improving patient outcomes.
基金Supported by the Peak Supporting Clinical Discipline of Shanghai Health Bureau,No.2023ZDFC0104the National Key R&D Program of China,No.2019YFA0110601.
文摘BACKGROUND Acute lung injury(ALI)is a fatal and heterogeneous disease.While bone marrow mesenchymal stem cells(BMSCs)have shown promise in ALI repair,their efficacy is compromised by a high apoptotic percentage.Preliminary findings have indicated that long noncoding RNA(lncRNA)-ENST expression is markedly downregulated in MSCs under ischemic and hypoxic conditions,establishing a rationale for in vitro exploration.AIM To elucidate the role of lncRNA-ENST00000517482(lncRNA-ENST)in modulating MSC apoptosis.METHODS Founded on ALI in BEAS-2B cells with lipopolysaccharide,this study employed a transwell co-culture system to study BMSC tropism.BMSCs were genetically modified to overexpress or knockdown lncRNA-ENST.After analyzing the effects on autophagy,apoptosis and cell viability,the lncRNA-ENST/miR-539/c-MYC interaction was confirmed by dual-luciferase assays.RESULTS These findings have revealed a strong correlation between lncRNA-ENST levels and the apoptotic and autophagic status of BMSCs.On the one hand,the overexpression of lncRNA-ENST,as determined by Cell Counting Kit-8 assays,increased the expression of autophagy markers LC3B,ATG7,and ATG5.On the other hand,it reduced apoptosis and boosted BMSC viability.In co-cultures with BEAS-2B cells,lncRNA-ENST overexpression also improved cell vitality.Additionally,by downregulating miR-539 and upregulating c-MYC,lncRNA-ENST was found to influence mitochondrial membrane potential,enhance BMSC autophagy,mitigate apoptosis and lower the secretion of proinflammatory cytokines interleukin-6 and interleukin-1β.Collectively,within the in vitro framework,these results have highlighted the therapeutic potential of BMSCs in ALI and the pivotal regulatory role of lncRNA-ENST in miR-539 and apoptosis in lipopolysaccharide-stimulated BEAS-2B cells.CONCLUSION Our in vitro results show that enhanced lncRNA ENST expression can promote BMSC proliferation and viability by modulating the miR-539/c-MYC axis,reduce apoptosis and induce autophagy,which has suggested its therapeutic potential in the treatment of ALI.
基金Supported by Capital Fund Project for Clinical Diagnosis and Treatment Technology Research and Translational Application,No.Z201100005520091.
文摘Publications of Soufan et al and Kristjánsson et al in the World Journal of Orthopedics on mesenchymal stem cell(MSC)therapy for osteoarthritis(OA)represent a significant exploration of regenerative medicine’s potential in OA treatment.In their research,it is highlighted that MSCs can alleviate OA symptoms and even regenerate cartilage,potentially reversing the disease.They also compared the efficacy of three MSC subtypes,emphasizing the therapeutic advantages of adipose-derived MSCs.MSC injections,a novel and less invasive alternative to traditional treatments such as chondrocyte transplantation or arthroplasty,have a low cost,low risks,and favorable outcomes,presenting a promising approach for OA patients.Additionally,we stressed that the efficacy evaluation criteria,heterogeneity,safety,and other factors must be carefully considered to further advance the clinical translation of MSC therapy for OA.
基金Supported by the National Natural Science Foundation of China,No.32060232and the Natural Science Foundation of Jiangxi Province,No.20212BAB206075.
文摘BACKGROUND Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)can traverse the blood-brain barrier due to their small size.This characteristic makes them a research hotspot for the treatment of Parkinson’s disease(PD)and is expected to be a potentially revolutionary strategy for treating PD.Despite this,no summary of clinical trial results has been reported.AIM To assess the efficacy and durability of MSC-EVs in treating PD.METHODS Systematic searches were conducted in four electronic databases until June 2024 to collect studies on the use of MSC-EVs for this purpose.Thirteen relevant randomized controlled trials,encompassing 16 experiments,were selected for inclusion.RESULTS Behavioral assessments,including the rotarod and apomorphine turning behavior tests,indicated improvements in motor coordination(P<0.00001);the Pole test and the Wire-hang test showed enhanced limb motor agility and synchronization(P=0.003 and P<0.00001,respectively).Histopathologically,there was a reduction in inflammatory markers such as tumor necrosis factor-αand interleukin-6(P=0.03 and P=0.01,respectively)and an increase in tyrosine hydroxylase-positive cells in the lesion areas(P<0.00001).CONCLUSION MSC-EV therapy for PD is a gradual process,with significant improvements observable more than 2 weeks after administration and lasting at least 8 weeks.This study is the first to demonstrate the efficacy and durability of MSC-EV treatment in PD.
文摘In this editorial,we comment on the recent article by Xiao et al,focusing on their investigation into whether the therapeutic efficacy of serum-free human umbilical cord mesenchymal stem cells(MSCs)differs from that of serum-containing human umbilical cord MSCs in a mouse model of knee osteoarthritis(OA).The incidence of OA has significantly increased in recent years,primarily owing to sports-related injuries or degenerative diseases.However,the regenerative capacity of articular cartilage remains limited,necessitating artificial joint replacement for patients with advanced OA to enhance the quality of life.MSCs have been widely used in the clinical treatment of OA owing to their multidirectional differentiation potential and immunomodulatory effects.The focus of this paper lies in elucidating the mechanism underlying MSC transplantation for the treatment of knee OA,while also addressing the challenges encountered in MSC therapy and outlining future directions.
基金Supported by the Natural Science Foundation of Shanghai,No.24ZR1459300(to Xiao-Ting Liang)and the Pyramid Talent Project,No.YQ677(to Yue Ding).
文摘This article discusses the study by Xiao et al,which investigated the therapeutic efficacy of serum-free cultured human umbilical cord mesenchymal stem cells(NhUCMSCs)in a mouse model of knee osteoarthritis.The results showed that NhUCMSCs alleviated osteoarthritis-related cartilage damage and inflammation comparably to both serum-cultured hUCMSCs and hyaluronic acid.While these findings broaden the potential clinical utility of N-hUCMSCs by circumventing certain drawbacks of serum-based cultures,the equivalence in efficacy raises important questions.First,how do N-hUCMSCs differ phenotypically from serum-cultured hUCMSCs,particularly in terms of proliferation rate,replicative capacity,and senescence profile?Second,what advantages might N-hUCMSCs offer over hyaluronic acid-a well-established therapy-beyond avoiding xenogeneic components and ethical concerns?Future research should focus on longterm phenotypic stability,sustained functional benefits,safety profiles,and mechanistic insights to ascertain whether N-hUCMSCs can surpass current standards of care.
基金Supported by the National Natural Science Foundation of China,No.82072537the General Project of Hunan Natural Science Foundation,No.2022JJ30412 and No.2021JJ30464.
文摘Exosomes(Exos)are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication.They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions.Exos derived from mesenchymal stem cells(MSCs)have significant immunomodulatory properties.They effectively regulate immune responses by modulating both innate and adaptive immunity.These Exos can inhibit excessive inflammatory responses and promote tissue repair.Moreover,they participate in antigen presentation,which is essential for activating immune responses.The cargo of these Exos,including ligands,proteins,and microRNAs,can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response.By inhibiting lymphocyte proliferation,acting on macrophages,and increasing the population of regulatory T cells,these Exos contribute to maintaining immune and metabolic homeostasis.Furthermore,they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells,which holds potential for immunotherapy applications.Given the immense therapeutic potential of MSC-derived Exos,this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control,tumor suppression,and autoimmune disease management.This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos,offering theoretical references for their future clinical utilization as cell-free drug preparations.
文摘Acute kidney injury(AKI)is a clinical syndrome characterized by a rapid deterioration in kidney function and has a significant impact on patient health and survival.Mesenchymal stem cells(MSCs)have the potential to enhance renal function by suppressing the expression of cell cycle inhibitors and reducing the expression of senescence markers and microRNAs via paracrine and endocrine mechanisms.MSC-derived exosomes can alleviate AKI symptoms by regulating DNA damage,apoptosis,and other related signaling pathways through the delivery of proteins,microRNAs,long-chain noncoding RNAs,and circular RNAs.This technique is both safe and effective.MSC-derived exosomes may have great application prospects in the treatment of AKI.Understanding the underlying mechanisms will foster the development of new and promising therapeutic strategies against AKI.This review focused on recent advancements in the role of MSCs in AKI repair as well as the mechanisms underlying the role of MSCs and their secreted exosomes.It is anticipated that novel and profound insights into the functionality of MSCs and their derived exosomes will emerge.
基金Shanghai Natural Science Foundation,No.21ZR1452300the Clinical Research Innovation Plan of Shanghai General Hospital,No.CCTR-2022B04.
文摘BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage.However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells(BMSCs),is less reported.BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis;however,the impairment caused by sepsis remains unknown.AIM To investigate the effects of sepsis on BMSCs and the underlying mechanisms.METHODS BMSCs were obtained from healthy donors and patients with sepsis.We compared the self-renewal capacity,differentiation potential,and hematopoietic supportive ability in vitro.Senescence of septic BMSCs was assessed usingβ-galactosidase staining,senescence-associated secretory phenotype,intracellular reactive oxygen species levels,and the expression of P16 and P21.Finally,the changes in septic BMSCs after nicotinamide adenine dinucleotide(NAD)treatment were evaluated.RESULTS Septic BMSCs showed decreased proliferation and self-renewal,bias towards adipogenic differentiation,and weakened osteogenic differentiation.Additionally,hematopoietic supportive capacity declines in sepsis.The levels of aging markers were significantly higher in the septic BMSCs.After NAD treatment,the proliferation capacity of septic BMSCs showed a recovery trend,with increased osteogenic and hematopoietic supportive capacities.Sepsis resulted in decreased expression of sirtuin 3(SIRT3)in BMSCs,whereas NAD treatment restored SIRT3 expression,enhanced superoxide dismutase enzyme activity,reduced intracellular reactive oxygen species levels,maintained mitochondrial stability and function,and ultimately rejuvenated septic BMSCs.CONCLUSION Sepsis accelerates the aging of BMSCs,as evidenced by a decline in self-renewal and osteogenic capabilities,as well as weakened hematopoietic support functions.These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway.
基金Supported by Basic Research Plan of Yunnan Province,No.202201AT070059National Natural Science Foundation of China,No.81760407Science and Technology Talent and Platform Plan of Yunnan Provincial Department of Science and Technology,No.202205AC160066.
文摘BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA treatments,their use is limited by the condition itself,and understanding of the underlying mechanisms of OA is lacking.AIM To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.METHODS Sodium iodoacetate was injected into rat articulations to construct an animal model of OA.Interleukin(IL)-1βwas used to induce human chondrocytes(CHON-001)to construct an OA chondrocyte model.Exosomes in hUC-MSCs were isolated using Ribo™Exosome Isolation Reagent.Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins,and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay,terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho-sphate-nick end labelling staining and hematoxylin and eosin staining.RESULTS hUC-MSC-derived exosomes(hUC-MSC-Exos)inhibited the expression of IL-1β-induced inflammatory cytokines,namely,IL-6,IL-8 and tumor necrosis factor-α.hUC-MSC-Exos also improved the viability but inhibited the apoptosis of CHON-001 cells,improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo.Mechanistically,hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p,thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway,alleviating IL-1β-induced chondrocyte inflammation and apoptosis,and ultimately improving the development of OA.CONCLUSION hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway.The present findings suggest that miR-199a-3p delivery by hUC-MSCExos may be a novel strategy for the treatment of OA.
基金National Natural Science Foundation of China,No.81873934and Jinan Science and Technology Planning Project,No.202225065.
文摘BACKGROUND Mesenchymal stem cells,found in various tissues,possess significant healing and immunomodulatory properties,influencing macrophage polarization,which is essential for wound repair.However,chronic wounds present significant therapeutic challenges,requiring novel strategies to improve healing outcomes.AIM To investigate the potential of fetal dermal mesenchymal stem cells(FDMSCs)in enhancing wound healing through modulation of macrophage polarization,specifically by promoting the M2 phenotype to address inflammatory responses in chronic wounds.METHODS FDMSCs were isolated from BalB/C mice and co-cultured with RAW264.7 macrophages to assess their effects on macrophage polarization.Flow cytometry,quantitative reverse transcriptase polymerase chain reaction,and histological analyses were employed to evaluate shifts in macrophage phenotype and wound healing in a mouse model.Statistical analysis was performed using GraphPad Prism.RESULTS FDMSCs induced macrophage polarization from the M1 to M2 phenotype,as demonstrated by a reduction in proinflammatory markers(inducible nitric oxide synthase,interleukin-6)and an increase in anti-inflammatory markers[mannose receptor(CD206),arginase-1]in co-cultured RAW264.7 macrophages.These shifts were confirmed by flow cytometry.In an acute skin wound model,FDMSC-treated mice exhibited faster wound healing,enhanced collagen deposition,and improved vascular regeneration compared to controls.Significantly higher expression of arginase-1 further indicated an enriched M2 macrophage environment.CONCLUSION FDMSCs effectively modulate macrophage polarization from M1 to M2,reduce inflammation,and enhance tissue repair,demonstrating their potential as an immunomodulatory strategy in wound healing.These findings highlight the promising therapeutic application of FDMSCs in managing chronic wounds.
基金Supported by the Peak Disciplines(Type IV)of Institutions of Higher Learning in Shanghai and the China Postdoctoral Science Foundation,No.2022M722409.
文摘BACKGROUND Mesenchymal stem cells(MSCs)and their secretome have significant potential in promoting hair follicle development.However,the effects of MSC therapy have been reported to vary due to their heterogeneous characteristics.Different sources of MSCs or culture systems may cause heterogeneity of exosomes.AIM To define the potential of human adipose-derived MSC exosomes(hADSC-Exos)and human umbilical cord-derived MSC exosomes(hUCMSC-Exos)for improving dermal papillary cell proliferation in androgenetic alopecia.METHODS We conducted liquid chromatography-mass spectrometry proteomic analysis of hADSC-Exos and hUCMSC-Exos.Liquid chromatography-mass spectrometry suggested that hADSC-Exos were related to metabolism and immunity.Additionally,the hADSC-Exo proteins regulated the cell cycle and other 9 functional groups.RESULTS We verified that hADSC-Exos inhibited glycogen synthase kinase-3βexpression by activating the Wnt/β-catenin signaling pathway via cell division cycle protein 42,and enhanced dermal papillary cell proliferation and migration.Excess dihydrotestosterone caused androgenetic alopecia by shortening the hair follicle growth phase,but hADSC-Exos reversed these effects.CONCLUSION This study indicated that hair development is influenced by hADSC-Exo-mediated cell-to-cell communication via the Wnt/β-catenin pathway.
基金American Heart Association Award,No.24IVPHA1288417and FCT Fellowships,No.2022.13253.BDANA.
文摘The potential of induced pluripotent stem cells(iPSCs)for modeling and treating metabolic associated fatty liver disease(MAFLD)and metabolic associated steatohepatitis(MASH)is emerging.MAFLD is a growing global health concern,currently with limited treatment options.While primary mesenchymal stem cells hold promise,iPSCs offer a versatile alternative due to their ability to differentiate into various cell types,including iPSC-derived mesenchymal stem cells.However,challenges remain,including optimizing differentiation protocols,ensuring cell safety,and addressing potential tumorigenicity risks.In addition,iPSCs offer the possibility to generate complex cellular models,including three-dimensional organoid models,which are closer representations of the human disease than animal models.Those models would also be valuable for drug discovery and personalized medicine approaches.Overall,iPSCs and their derivatives offer new perspectives for advancing MAFLD/MASH research and developing novel therapeutic strategies.Further research is needed to overcome current limitations and translate this potential into effective clinical applications.
