Dental tissues development involves two distinct cell lineages:mesenchymal cells(derived from the cranial neural crest)and epithelial cells(derived from oral ectoderm and pharyngeal epithelium).Emerging evidence highl...Dental tissues development involves two distinct cell lineages:mesenchymal cells(derived from the cranial neural crest)and epithelial cells(derived from oral ectoderm and pharyngeal epithelium).Emerging evidence highlights the remarkable functional heterogeneity of cranial neural crest-derived dental mesenchymal stem cells(DMSCs),exhibiting pluripotency,self-renewal,and differentiation capacities.This heterogeneity enables a single DMSC population to generate specialized subpopulations with unique roles in teeth and periodontal tissues formation.Significant progress has been made in characterizing six major types of DMSCs and two populations of closely related cells:Tooth germ progenitor cells(TGPCs)and dental follicle stem cells(DFSCs),critical during early morphogenesis;Stem cells from human exfoliated deciduous teeth(SHEDs)and apical papilla stem cells(SCAPs),pivotal for root development;Dental pulp stem cells(DPSCs),periodontal ligament stem cells(PDLSCs),gingival mesenchymal stem cells(GMSCs)and alveolar bone mesenchymal stem cells(ABMSCs),essential for maintaining and regenerating mature dental tissues.A key breakthrough has unveiled the development and hierarchy of DMSCs by applying new techniques like single-cell RNA sequencing(scRNA-seq).To integrate insights into the development of teeth and periodontal tissues,this review synthesizes current knowledge on both developmental heterogeneity and subpopulation heterogeneity within DMSCs and related cells.These insights not only advance fundamental understanding of the developmental mechanisms of teeth and periodontal tissues,but also establish a promising framework for achieving more efficient tissue regeneration and repair engineering.展开更多
Multipotent stromal cells,otherwise known as mesenchymal stem cells(MSCs),have been widely studied for their regenerative potential across multiple tissues,including the nervous system(Caplan,2017).Reports suggesting ...Multipotent stromal cells,otherwise known as mesenchymal stem cells(MSCs),have been widely studied for their regenerative potential across multiple tissues,including the nervous system(Caplan,2017).Reports suggesting that MSCs can differentiate into neurons and glia spurred optimism towards their future therapeutic application in nervous system disorders.Despite extensive research,however,the precise cellular mechanisms underlying their neural differentiation potential are unclear(George et al.,2019).展开更多
Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function...Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease,acute ischemic stroke,and Parkinson’s disease.In addition,mesenchymal stem cell therapy modulates the immune system,reduces neuroinflammation,and improves resolution of brain lesions by cells of the macrophage lineage.Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition,which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation.Therefore,we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response.In this study,we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy(Tg-SwDI/B).Bone marrow mesenchymal stem cell treatment improved cognitive function,reduced neuroinflammation,and maintained blood-brain barrier integrity in Tg-SwDI/B mice.Mechanistically,bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes,in a process known as mitocytosis,thereby preserving mitochondrial quality within the neutrophils.Mitochondrial damage in neutrophils leads to cellular injury,including the generation of reactive oxygen species and the formation of neutrophil extracellular traps.Neutrophils activate mitocytosis to promote mitochondrial renewal,which further enhances their own clearance by macrophage lineage cells.Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy,as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.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
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
Alzheimer's disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists.We have previously reported that mesenchymal stem cell-derived extracellular vesicles del...Alzheimer's disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists.We have previously reported that mesenchymal stem cell-derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a-nuclear receptor subfamily 4 group A member 3 axis;however,it remains unclear how NR4A3 drives inflammation.Herein,we engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer's disease.In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells,extracellular vesicles overexpressing miR-146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression,nuclear factor(NF)-κB activation,and caspase-3/apoptosis regulator BAX signaling.These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice.In addition,extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes,reduced amyloid-βand phosphorylated tau expression,lowered the number of apoptotic cells in the hippocampus,and improved the cognitive function of these Alzheimer's disease model mice.Mechanistically,miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling.Furthermore,NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling.The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression.Finally,NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction.Collectively,these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer's disease by exerting anti-inflammatory effects via the NR4A3-nuclear factor-κB axis.They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.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
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
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 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
Advanced therapy medicinal products are biological products that require rigorous long-term monitoring of safety and efficacy due to their sustained effects.The development of tissue-engineered products demands carefu...Advanced therapy medicinal products are biological products that require rigorous long-term monitoring of safety and efficacy due to their sustained effects.The development of tissue-engineered products demands careful consideration of tissue-specific properties,surgical requirements,biomaterial compatibility,host tissue integration,and potential immune responses.In this study,we developed and evaluated the safety and efficacy of 3D-bioprinted constructs containing cells for bone regeneration in preclinical models.Three types of human mesenchymal stem cells(bone marrow-derived,adipose-derived,and nasal turbinate-derived)were combined with varying concentrations of collagen and polycaprolactone.Safety assessments included comprehensive tumorigenicity evaluations involving cell viability assays,protein quantification,and whole-genome sequencing under multiple conditions to confirm genetic stability and mitigate tumorigenic risks.Short-term toxicity was evaluated by subcutaneous implantation in nude mice,with blood and serum analyses confirming the absence of acute toxicity or histological abnormalities in major organs.Efficacy studies in rabbits exhibited safety through post-transplantation analyses,with 6-month tissue analyses showing significantly elevated expression of osteopontin and runt-related transcription factor 2(RUNX2)proteins in constructs containing human nasal turbinate-derived mesenchymal stem cells,indicating successful tissue integration and bone-specific marker expression.Long-term follow-up confirmed construct integrity and sustained bone formation.These findings highlight the importance of comprehensive safety and efficacy evaluations across cell types and construct compositions in the development of 3D-bioprinted constructs for bone regeneration.This study establishes a systematic framework for material selection and validation in preclinical stages,providing a foundation for future clinical applications in regenerative medicine and tissue engineering.展开更多
Mesenchymal stem cells(MSCs) are widely utilized in disease treatment and regenerative medicine due to their potent immunomodulatory properties and capacity for tissue repair.However, limitations—including insufficie...Mesenchymal stem cells(MSCs) are widely utilized in disease treatment and regenerative medicine due to their potent immunomodulatory properties and capacity for tissue repair.However, limitations—including insufficient migratory capacity, suboptimal survival, proliferation, differentiation potential, and variable immunomodulatory responses—significantly hinder their clinical translation and therapeutic impact. Natural products have been shown to enhance MSC homing, stress resilience, immune regulation, and lineage-specific differentiation through multi-target mechanisms, thereby emerging as promising, safe, and practical strategies to improve the in vivo performance of MSC-based therapies. This review examines the key translational challenges associated with MSCs, elucidates the mechanistic basis by which natural products regulate the in vivo fate of MSCs, and explores the potential of integrating natural product adjuvants with MSC therapy for enhanced clinical outcomes.展开更多
Craniofacial bone regeneration remains a major clinical challenge,yet the identity of orofacial mesenchymal stem/stromal cells(OMSCs)has not been fully elucidated.Here,we performed single-cell RNA sequencing(scRNA-seq...Craniofacial bone regeneration remains a major clinical challenge,yet the identity of orofacial mesenchymal stem/stromal cells(OMSCs)has not been fully elucidated.Here,we performed single-cell RNA sequencing(scRNA-seq)on mouse orofacial bone and identified multiple stromal cell clusters.Cell-cell communication mapping and trajectory inference uncovered the heterogeneity of OMSCs and functional divergence among subpopulations.We identified a previously unrecognized population,Smmhc-expressing mesenchymal stem/stromal cells(MSCs),at the earliest stage of the progenitor lineage trajectory.In vivo lineage tracing demonstrated that Smmhc+MSCs are multipotent,giving rise to osteoblasts,osteocytes,periodontal ligament(PDL)cells,and dental pulp cells.Targeted ablation of Smmhc+MSCs using SmmhcCreER;iDTR mouse model led to impaired orofacial bone development and disrupted orofacial tissue homeostasis,characterized by reduced osteogenic differentiation and non-cell autonomous reduction of bone resorption.Collectively,this study establishes a cellular atlas of OMSCs and identifies Smmhc+MSCs as a functionally indispensable subset for craniofacial bone homeostasis,orchestrating the dynamic balance between osteogenesis and bone resorption within the orofacial skeletal niche.展开更多
This is an erratum to the published paper entitled“Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycin-induced focal segmental glomerulosclerosis...This is an erratum to the published paper entitled“Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycin-induced focal segmental glomerulosclerosis”.Upon reexamining our original data,we have identified an error in the assembly of Figure 1F,where the glyceraldehyde-3-phosphate dehydrogenase loading control image was incorrectly placed due to a clerical oversight during figure preparation.This does not reflect any issue with the underlying experimental data.展开更多
Objectives:Schneiderian membrane-derived mesenchymal stem cells(SMMSCs)have been reported to be osteogenic progenitor cells in vitro.However,there is controversy regarding the intrinsic osteogenic capacity of the Schn...Objectives:Schneiderian membrane-derived mesenchymal stem cells(SMMSCs)have been reported to be osteogenic progenitor cells in vitro.However,there is controversy regarding the intrinsic osteogenic capacity of the Schneiderian membrane,and the bone formation potential of SMMSCs in vivo has never been reported.Therefore,in this study,we aimed to evaluate the contribution of the Schneiderian membrane to sinus floor elevation and to verify the function of SMMSCs in cranial bone defects.Materials and methods:Bilateral sinus floor elevation with chloromethyl-benzamidodialkylcarbocyanine(CM-Dil)labeling was performed in rabbits to assess Schneiderian membrane osteogenesis.Single-cell RNA sequencing was used to characterize human Schneiderian membrane cellular subsets.SMMSCs and bone marrow-derived mesenchymal stem cells(BMSCs)were transplanted into rabbit cranial defects with gelatin methacryloyl(GelMA)scaffolds and analyzed via micro-computed tomography(micro-CT)and histology.Results:Spontaneous bone formation adjacent to the Schneiderian membrane was observed.Single-cell analysis identified paired-related homeobox 1(PRRX1)progenitor clusters driving endosinus osteogenesis.SMMSCs exhibited earlier and superior bone regeneration compared with BMSCs,with higher tissue volume and bone volumeotal volume(BV/TV)ratios at four weeks after surgery.Conclusions:The Schneiderian membrane likely contributes to osteogenesis via PRRX1+progenitor lineages.SMMSCs promote accelerated early bone regeneration in cranial defects.This study provides the first in vivo validation of the osteogenic capacity of SMMSCs and defines their molecular identity at single-cell resolution.展开更多
Recent clinical and translational studies have increasingly highlighted the promise of combined stem cell strategies for neurorestoration following ischemic stroke.In this correspondence,we reflect on the recent trial...Recent clinical and translational studies have increasingly highlighted the promise of combined stem cell strategies for neurorestoration following ischemic stroke.In this correspondence,we reflect on the recent trial by Yang et al,which reported that co-transplantation of mesenchymal stem cells(MSCs)and neural stem cells(NSCs)yielded significantly greater functional recovery in patients with acute cerebral infarction,as evidenced by improvements in both Barthel Index and National Institutes of Health Stroke Scale scores.Notably,this dual-cell intervention was accompanied by robust elevation of angiogenic and neurotrophic mediators,particularly vascular endothelial growth factor and basic fibroblast growth factor,suggesting a biologically plausible mechanism for the observed clinical benefit.MSCs contribute through trophic support,immunomodulatory effects,and promotion of vascular regeneration,whereas NSCs primarily facilitate neuronal replacement and reorganization of neural circuits.Together,these mechanisms offer a comprehensive,multitargeted approach to address the multifactorial nature of stroke pathology.Building on this pivotal work,we call for mechanistic studies and multicenter randomized clinical trials to refine cell dosing,timing,and bioengineering strategies,paving the way for the clinical integration of MSC/NSC co-therapy as a next-generation regenerative treatment for stroke.展开更多
BACKGROUND Acute mesenteric ischemia(AMI)is associated with high mortality owing to delayed diagnosis and the absence of biomarkers capable of distinguishing disease subtypes or inflammatory burden.Mesenchymal stem ce...BACKGROUND Acute mesenteric ischemia(AMI)is associated with high mortality owing to delayed diagnosis and the absence of biomarkers capable of distinguishing disease subtypes or inflammatory burden.Mesenchymal stem cells(MSCs)exosomal circular RNAs(circRNAs)show diagnostic potential in other diseases.AIM To evaluate the utility of MSCs exosomal circRNAs in AMI,particularly for early detection and subtyping.METHODS Peripheral blood-derived MSCs(PBMSCs)from 80 patients with AMI(stratified by etiology:48 arterial AMI,32 venous AMI,36 early reversible,44 late necrotic)and 125 controls were obtained at initial hospital admission.Exosomal circRNAs were isolated via ultracentrifugation,validated by transmission electron microscopy and nanoparticle tracking analysis,and quantified by quantitative real-time polymerase chain reaction.Plasma intestinal fatty acid binding protein(IFABP),d-lactate,interleukin-6(IL-6),tumor necrosis factor-α,IFABP,D-lactate,IL-6,and neutrophil-to-lymphocyte ratio were measured.Pearson’s test was used to assess the diagnostic performance of receiver operating characteristic analysis.RESULTS Patients with AMI exhibited significantly elevated PBMSCs exosomal circ-Eya3(P<0.001)and reduced circEZH2_005 levels(P<0.001).Circ-Eya3 correlated positively with IFABP(r=0.606),D-lactate(r=0.384),IL-6(r=0.551),and neutrophil-to-lymphocyte ratio(r=0.601)(all P<0.001),whereas circEZH2_005 showed inverse correlations(r=-0.580 to-0.403;P<0.001).Critically,circEZH2_005 expression was lower in arterial AMI than in venous AMI(P=0.003).The combination of circ-Eya3,circEZH2_005,and D-lactate achieved excellent diagnostic accuracy(area under the curve=0.891).Post-reperfusion,circ-Eya3 increased(P<0.05),while circEZH2_005 decreased(P<0.05).CONCLUSION PBMSCs exosomal circ-Eya3 and circEZH2_005 serve as novel biomarkers for AMI,reflecting intestinal injury severity,systemic inflammation,and disease subtype.Their integration with D-lactate enables high-accuracy diagnosis,whereas differential expression across arterial/venous AMI and ischemia stages offers clinical utility for guiding intervention strategies.展开更多
Osteoarthritis(OA)remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking.Accumulating evidence positions mitochondrial dysfunction and impaired mitochondri...Osteoarthritis(OA)remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking.Accumulating evidence positions mitochondrial dysfunction and impaired mitochondrial quality control as central drivers of chondrocyte failure,extracellular matrix breakdown,and inflammation amplification.Mitophagy—particularly the phosphatase and tensin homolog-induced kinase 1(PINK1)/Parkin axis—has therefore emerged as an attractive,mechanistically grounded intervention point.In this context,synovial mesenchymal stem cell-derived exosomes(SMSC-Exos)represent a compelling cell-free platform capable of delivering functional biomolecules into inflamed cartilage microenvironments.Recent experimental work demonstrates that engineering SMSC-Exos to deliver the mitochondrial co-chaperone GrpE-like 1(GRPEL1)restores chondrocyte proliferative and migratory capacity under interleukin-1βstress,preserves anabolic extracellular matrix markers(collagen type II alpha 1/aggrecan),suppresses catabolic mediators(matrix metalloproteinase 13/A disintegrin and metalloproteinase with thrombospondin motifs 5),and mitigates oxidative damage while enhancing mitophagy signatures.Mechanistically,GRPEL1 directly associates with PINK1,and PINK1 knockdown attenuates the protective phenotype,supporting a GRPEL1-PINK1 coupling model.In vivo,intra-articular administration of GRPEL1-enriched SMSC-Exos improves histological cartilage integrity and mitophagy-related readouts in a rat OA model.Here,we synthesize mechanistic implications,highlight interpretive nuances(e.g.,mitophagy activation concurrent with membrane potential recovery),and outline translational priorities,including cargo quantification,mitophagy flux validation,dosingetention kinetics,manufacturing standardization,and biomarker-driven patient stratification.展开更多
BACKGROUND Bone marrow-derived mesenchymal stem cells(BMSCs)are a promising therapy for ulcerative colitis(UC).However,their clinical benefit is limited by inefficient homing to the inflamed colonic mucosa.Improving t...BACKGROUND Bone marrow-derived mesenchymal stem cells(BMSCs)are a promising therapy for ulcerative colitis(UC).However,their clinical benefit is limited by inefficient homing to the inflamed colonic mucosa.Improving the migration of BMSCs to sites of intestinal inflammation remains a key challenge in the development of cell-based treatments for UC.Tongxie Yaofang(TXYF),a traditional Chinese medicine formula,has been shown to relieve symptoms in UC patients.Our previous in vitro studies also showed that TXYF enhances the migratory capacity of BMSCs.However,whether TXYF enhances the therapeutic effect of BMSCs transplantation in UC,and the mechanisms involved,remain unclear.AIM To determine whether TXYF promotes the homing of BMSCs and improves experimental colitis,and to explore the underlying mechanisms.METHODS BMSCs from Sprague-Dawley rats were characterized via flow cytometry,and TXYF’s effects on migration were evaluated using scratch and Transwell assays.In a colitis model,the synergistic efficacy of TXYF and BMSCs was assessed through disease activity index,histology,immunohistochemistry,tracing,reverse transcriptionquantitative polymerase chain reaction,and western blotting.Furthermore,the stromal cell-derived factor 1(SDF-1)/C-X-C chemokine receptor type 4(CXCR4)axis was investigated using specific antagonists to elucidate the molecular mechanisms of this combinatorial therapy.RESULTS TXYF promoted the in vitro migration of BMSCs.In vivo,the combination of TXYF with BMSCs transplantation alleviated colitis symptoms in rats,improving inflammatory responses,colonic tissue damage,and mucosal barrier function.Our findings suggest that TXYF may enhance the migratory capacity of BMSCs by modulating the SDF-1/CXCR4 axis,thereby increasing their homing to the colonic mucosa.CONCLUSION This study demonstrates that TXYF can enhance the homing efficiency of exogenous BMSCs to the colonic mucosa,likely through the SDF-1/CXCR4 axis,which contributes to the mitigation of experimental colitis.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
基金supported by the National Natural Science Foundation of China(grant numbers U25A6003,82571128,82271008)Natural Science Foundation of Zhejiang Province(LR26H140001,ZCLQN25H1401).
摘要Dental tissues development involves two distinct cell lineages:mesenchymal cells(derived from the cranial neural crest)and epithelial cells(derived from oral ectoderm and pharyngeal epithelium).Emerging evidence highlights the remarkable functional heterogeneity of cranial neural crest-derived dental mesenchymal stem cells(DMSCs),exhibiting pluripotency,self-renewal,and differentiation capacities.This heterogeneity enables a single DMSC population to generate specialized subpopulations with unique roles in teeth and periodontal tissues formation.Significant progress has been made in characterizing six major types of DMSCs and two populations of closely related cells:Tooth germ progenitor cells(TGPCs)and dental follicle stem cells(DFSCs),critical during early morphogenesis;Stem cells from human exfoliated deciduous teeth(SHEDs)and apical papilla stem cells(SCAPs),pivotal for root development;Dental pulp stem cells(DPSCs),periodontal ligament stem cells(PDLSCs),gingival mesenchymal stem cells(GMSCs)and alveolar bone mesenchymal stem cells(ABMSCs),essential for maintaining and regenerating mature dental tissues.A key breakthrough has unveiled the development and hierarchy of DMSCs by applying new techniques like single-cell RNA sequencing(scRNA-seq).To integrate insights into the development of teeth and periodontal tissues,this review synthesizes current knowledge on both developmental heterogeneity and subpopulation heterogeneity within DMSCs and related cells.These insights not only advance fundamental understanding of the developmental mechanisms of teeth and periodontal tissues,but also establish a promising framework for achieving more efficient tissue regeneration and repair engineering.
摘要Multipotent stromal cells,otherwise known as mesenchymal stem cells(MSCs),have been widely studied for their regenerative potential across multiple tissues,including the nervous system(Caplan,2017).Reports suggesting that MSCs can differentiate into neurons and glia spurred optimism towards their future therapeutic application in nervous system disorders.Despite extensive research,however,the precise cellular mechanisms underlying their neural differentiation potential are unclear(George et al.,2019).
基金Guangdong Basic and Applied Basic Research Foundation,No.2023A1515110543(to XK)National Natural Science Foundation of China,Nos.82471335 and 82171307(to ZL)+3 种基金Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0504803(to ZL)Science and Technology Program of Guangzhou,No.202201020588(to ZL)China Postdoctoral Science Foundation,No.2023M744023(to MH)Guangzhou Municipal School(Hospital)Joint Funding(Dengfeng Hospital)Municipal Key Laboratory Construction Project,No.202102010009(to ZL).
摘要Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease,acute ischemic stroke,and Parkinson’s disease.In addition,mesenchymal stem cell therapy modulates the immune system,reduces neuroinflammation,and improves resolution of brain lesions by cells of the macrophage lineage.Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition,which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation.Therefore,we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response.In this study,we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy(Tg-SwDI/B).Bone marrow mesenchymal stem cell treatment improved cognitive function,reduced neuroinflammation,and maintained blood-brain barrier integrity in Tg-SwDI/B mice.Mechanistically,bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes,in a process known as mitocytosis,thereby preserving mitochondrial quality within the neutrophils.Mitochondrial damage in neutrophils leads to cellular injury,including the generation of reactive oxygen species and the formation of neutrophil extracellular traps.Neutrophils activate mitocytosis to promote mitochondrial renewal,which further enhances their own clearance by macrophage lineage cells.Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy,as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.
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).
摘要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.
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)。
摘要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supported by the Natural Science Foundation of Hunan Province,Nos.2025JJ81006(to JZ),2025JJ90150(to QX),2022JJ30522(to QX),2022JJ70034(to ZW)Clinical Medical Technology Innovation Guidance Project of Hunan Province,No.2021SK51813(to BW)。
摘要Alzheimer's disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists.We have previously reported that mesenchymal stem cell-derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a-nuclear receptor subfamily 4 group A member 3 axis;however,it remains unclear how NR4A3 drives inflammation.Herein,we engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer's disease.In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells,extracellular vesicles overexpressing miR-146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression,nuclear factor(NF)-κB activation,and caspase-3/apoptosis regulator BAX signaling.These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice.In addition,extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes,reduced amyloid-βand phosphorylated tau expression,lowered the number of apoptotic cells in the hippocampus,and improved the cognitive function of these Alzheimer's disease model mice.Mechanistically,miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling.Furthermore,NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling.The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression.Finally,NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction.Collectively,these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer's disease by exerting anti-inflammatory effects via the NR4A3-nuclear factor-κB axis.They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.
基金supported by the National Key R&D Program of China,Nos.2017YFA0104302(to NG and XM)and 2017YFA0104304(to BW and ZZ)
摘要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.
摘要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.
摘要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 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).
摘要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 a grant(No.RS-2024-00397128)from the Ministry of Food and Drug Safety in 2024supported by the National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT(No.2021M3F7A1083232)supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(Nos.RS-2023-00215891 and 2022R1A2C2008149).
摘要Advanced therapy medicinal products are biological products that require rigorous long-term monitoring of safety and efficacy due to their sustained effects.The development of tissue-engineered products demands careful consideration of tissue-specific properties,surgical requirements,biomaterial compatibility,host tissue integration,and potential immune responses.In this study,we developed and evaluated the safety and efficacy of 3D-bioprinted constructs containing cells for bone regeneration in preclinical models.Three types of human mesenchymal stem cells(bone marrow-derived,adipose-derived,and nasal turbinate-derived)were combined with varying concentrations of collagen and polycaprolactone.Safety assessments included comprehensive tumorigenicity evaluations involving cell viability assays,protein quantification,and whole-genome sequencing under multiple conditions to confirm genetic stability and mitigate tumorigenic risks.Short-term toxicity was evaluated by subcutaneous implantation in nude mice,with blood and serum analyses confirming the absence of acute toxicity or histological abnormalities in major organs.Efficacy studies in rabbits exhibited safety through post-transplantation analyses,with 6-month tissue analyses showing significantly elevated expression of osteopontin and runt-related transcription factor 2(RUNX2)proteins in constructs containing human nasal turbinate-derived mesenchymal stem cells,indicating successful tissue integration and bone-specific marker expression.Long-term follow-up confirmed construct integrity and sustained bone formation.These findings highlight the importance of comprehensive safety and efficacy evaluations across cell types and construct compositions in the development of 3D-bioprinted constructs for bone regeneration.This study establishes a systematic framework for material selection and validation in preclinical stages,providing a foundation for future clinical applications in regenerative medicine and tissue engineering.
基金supported by the Leading Technology Foundation Research Project of Jiangsu Province (No. BK20232035)the Key Project of Basic Research Program of Jiangsu Province(No. BK20243061)+1 种基金the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University (No.SKLNMZZ202302)the Haihe Laboratory of Cell Ecosystem Innovation Fund (No. 22HHXBSS00005)。
摘要Mesenchymal stem cells(MSCs) are widely utilized in disease treatment and regenerative medicine due to their potent immunomodulatory properties and capacity for tissue repair.However, limitations—including insufficient migratory capacity, suboptimal survival, proliferation, differentiation potential, and variable immunomodulatory responses—significantly hinder their clinical translation and therapeutic impact. Natural products have been shown to enhance MSC homing, stress resilience, immune regulation, and lineage-specific differentiation through multi-target mechanisms, thereby emerging as promising, safe, and practical strategies to improve the in vivo performance of MSC-based therapies. This review examines the key translational challenges associated with MSCs, elucidates the mechanistic basis by which natural products regulate the in vivo fate of MSCs, and explores the potential of integrating natural product adjuvants with MSC therapy for enhanced clinical outcomes.
基金supported by grants from the National Natural Science Foundation of China(NSFC)(82370945,82571077,82171001,and 82222015)Natural Science Foundation of Sichuan Province(2024NSFSC0545)+1 种基金Youth Innovation Project of Sichuan Province(Q23007)Funding from West China School/Hospital of Stomatology,Sichuan University(RCDWJS2024-4)。
摘要Craniofacial bone regeneration remains a major clinical challenge,yet the identity of orofacial mesenchymal stem/stromal cells(OMSCs)has not been fully elucidated.Here,we performed single-cell RNA sequencing(scRNA-seq)on mouse orofacial bone and identified multiple stromal cell clusters.Cell-cell communication mapping and trajectory inference uncovered the heterogeneity of OMSCs and functional divergence among subpopulations.We identified a previously unrecognized population,Smmhc-expressing mesenchymal stem/stromal cells(MSCs),at the earliest stage of the progenitor lineage trajectory.In vivo lineage tracing demonstrated that Smmhc+MSCs are multipotent,giving rise to osteoblasts,osteocytes,periodontal ligament(PDL)cells,and dental pulp cells.Targeted ablation of Smmhc+MSCs using SmmhcCreER;iDTR mouse model led to impaired orofacial bone development and disrupted orofacial tissue homeostasis,characterized by reduced osteogenic differentiation and non-cell autonomous reduction of bone resorption.Collectively,this study establishes a cellular atlas of OMSCs and identifies Smmhc+MSCs as a functionally indispensable subset for craniofacial bone homeostasis,orchestrating the dynamic balance between osteogenesis and bone resorption within the orofacial skeletal niche.
基金Supported by the National Natural Science Foundation of China,No.82205002 and No.82104662the Science and Technology Project of Sichuan Province,No.2022YFS0621+1 种基金Luzhou-Southwest Medical University Science and Technology Strategic Cooperation Project,No.2021 LZXNYD-P04the Southwest Medical University of Affiliated Traditional Medicine Hospital Project,No.2022-CXTD-03。
摘要This is an erratum to the published paper entitled“Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycin-induced focal segmental glomerulosclerosis”.Upon reexamining our original data,we have identified an error in the assembly of Figure 1F,where the glyceraldehyde-3-phosphate dehydrogenase loading control image was incorrectly placed due to a clerical oversight during figure preparation.This does not reflect any issue with the underlying experimental data.
基金supported by the National Key Research and Development Program of China(No.2023YFB3813003)the Innovative Talent of Zhejiang Provincial Health Commission,the Research and Development Project of Stomatology Hospital Zhejiang University School of Medicine(No.RD2023DLYB02)the National Natural Science Foundation of China(No.82430031).
摘要Objectives:Schneiderian membrane-derived mesenchymal stem cells(SMMSCs)have been reported to be osteogenic progenitor cells in vitro.However,there is controversy regarding the intrinsic osteogenic capacity of the Schneiderian membrane,and the bone formation potential of SMMSCs in vivo has never been reported.Therefore,in this study,we aimed to evaluate the contribution of the Schneiderian membrane to sinus floor elevation and to verify the function of SMMSCs in cranial bone defects.Materials and methods:Bilateral sinus floor elevation with chloromethyl-benzamidodialkylcarbocyanine(CM-Dil)labeling was performed in rabbits to assess Schneiderian membrane osteogenesis.Single-cell RNA sequencing was used to characterize human Schneiderian membrane cellular subsets.SMMSCs and bone marrow-derived mesenchymal stem cells(BMSCs)were transplanted into rabbit cranial defects with gelatin methacryloyl(GelMA)scaffolds and analyzed via micro-computed tomography(micro-CT)and histology.Results:Spontaneous bone formation adjacent to the Schneiderian membrane was observed.Single-cell analysis identified paired-related homeobox 1(PRRX1)progenitor clusters driving endosinus osteogenesis.SMMSCs exhibited earlier and superior bone regeneration compared with BMSCs,with higher tissue volume and bone volumeotal volume(BV/TV)ratios at four weeks after surgery.Conclusions:The Schneiderian membrane likely contributes to osteogenesis via PRRX1+progenitor lineages.SMMSCs promote accelerated early bone regeneration in cranial defects.This study provides the first in vivo validation of the osteogenic capacity of SMMSCs and defines their molecular identity at single-cell resolution.
摘要Recent clinical and translational studies have increasingly highlighted the promise of combined stem cell strategies for neurorestoration following ischemic stroke.In this correspondence,we reflect on the recent trial by Yang et al,which reported that co-transplantation of mesenchymal stem cells(MSCs)and neural stem cells(NSCs)yielded significantly greater functional recovery in patients with acute cerebral infarction,as evidenced by improvements in both Barthel Index and National Institutes of Health Stroke Scale scores.Notably,this dual-cell intervention was accompanied by robust elevation of angiogenic and neurotrophic mediators,particularly vascular endothelial growth factor and basic fibroblast growth factor,suggesting a biologically plausible mechanism for the observed clinical benefit.MSCs contribute through trophic support,immunomodulatory effects,and promotion of vascular regeneration,whereas NSCs primarily facilitate neuronal replacement and reorganization of neural circuits.Together,these mechanisms offer a comprehensive,multitargeted approach to address the multifactorial nature of stroke pathology.Building on this pivotal work,we call for mechanistic studies and multicenter randomized clinical trials to refine cell dosing,timing,and bioengineering strategies,paving the way for the clinical integration of MSC/NSC co-therapy as a next-generation regenerative treatment for stroke.
基金Supported by the Joint Development of Disciplines by Jiaxing City and Provincial Governmentthe National Key Clinical Specialty Construction Project,No.2023-GJZK-001.
摘要BACKGROUND Acute mesenteric ischemia(AMI)is associated with high mortality owing to delayed diagnosis and the absence of biomarkers capable of distinguishing disease subtypes or inflammatory burden.Mesenchymal stem cells(MSCs)exosomal circular RNAs(circRNAs)show diagnostic potential in other diseases.AIM To evaluate the utility of MSCs exosomal circRNAs in AMI,particularly for early detection and subtyping.METHODS Peripheral blood-derived MSCs(PBMSCs)from 80 patients with AMI(stratified by etiology:48 arterial AMI,32 venous AMI,36 early reversible,44 late necrotic)and 125 controls were obtained at initial hospital admission.Exosomal circRNAs were isolated via ultracentrifugation,validated by transmission electron microscopy and nanoparticle tracking analysis,and quantified by quantitative real-time polymerase chain reaction.Plasma intestinal fatty acid binding protein(IFABP),d-lactate,interleukin-6(IL-6),tumor necrosis factor-α,IFABP,D-lactate,IL-6,and neutrophil-to-lymphocyte ratio were measured.Pearson’s test was used to assess the diagnostic performance of receiver operating characteristic analysis.RESULTS Patients with AMI exhibited significantly elevated PBMSCs exosomal circ-Eya3(P<0.001)and reduced circEZH2_005 levels(P<0.001).Circ-Eya3 correlated positively with IFABP(r=0.606),D-lactate(r=0.384),IL-6(r=0.551),and neutrophil-to-lymphocyte ratio(r=0.601)(all P<0.001),whereas circEZH2_005 showed inverse correlations(r=-0.580 to-0.403;P<0.001).Critically,circEZH2_005 expression was lower in arterial AMI than in venous AMI(P=0.003).The combination of circ-Eya3,circEZH2_005,and D-lactate achieved excellent diagnostic accuracy(area under the curve=0.891).Post-reperfusion,circ-Eya3 increased(P<0.05),while circEZH2_005 decreased(P<0.05).CONCLUSION PBMSCs exosomal circ-Eya3 and circEZH2_005 serve as novel biomarkers for AMI,reflecting intestinal injury severity,systemic inflammation,and disease subtype.Their integration with D-lactate enables high-accuracy diagnosis,whereas differential expression across arterial/venous AMI and ischemia stages offers clinical utility for guiding intervention strategies.
基金Supported by Key Scientific Research Projects of Colleges and Universities in Henan Province,No.26A320038Henan Province Medical Science and Technology Research Plan Project(Joint Construction),No.LHGJ20250403,No.LHGJ20220566,and No.LHGJ20240365+1 种基金Key Research and Development Program of Henan Province,No.231111311000the Medical Education Research Project in Henan Province,No.WJLX2023079.
摘要Osteoarthritis(OA)remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking.Accumulating evidence positions mitochondrial dysfunction and impaired mitochondrial quality control as central drivers of chondrocyte failure,extracellular matrix breakdown,and inflammation amplification.Mitophagy—particularly the phosphatase and tensin homolog-induced kinase 1(PINK1)/Parkin axis—has therefore emerged as an attractive,mechanistically grounded intervention point.In this context,synovial mesenchymal stem cell-derived exosomes(SMSC-Exos)represent a compelling cell-free platform capable of delivering functional biomolecules into inflamed cartilage microenvironments.Recent experimental work demonstrates that engineering SMSC-Exos to deliver the mitochondrial co-chaperone GrpE-like 1(GRPEL1)restores chondrocyte proliferative and migratory capacity under interleukin-1βstress,preserves anabolic extracellular matrix markers(collagen type II alpha 1/aggrecan),suppresses catabolic mediators(matrix metalloproteinase 13/A disintegrin and metalloproteinase with thrombospondin motifs 5),and mitigates oxidative damage while enhancing mitophagy signatures.Mechanistically,GRPEL1 directly associates with PINK1,and PINK1 knockdown attenuates the protective phenotype,supporting a GRPEL1-PINK1 coupling model.In vivo,intra-articular administration of GRPEL1-enriched SMSC-Exos improves histological cartilage integrity and mitophagy-related readouts in a rat OA model.Here,we synthesize mechanistic implications,highlight interpretive nuances(e.g.,mitophagy activation concurrent with membrane potential recovery),and outline translational priorities,including cargo quantification,mitophagy flux validation,dosingetention kinetics,manufacturing standardization,and biomarker-driven patient stratification.
基金Supported by the Basic Public Welfare Research Program of Zhejiang Province,No.LQ23H270008.
摘要BACKGROUND Bone marrow-derived mesenchymal stem cells(BMSCs)are a promising therapy for ulcerative colitis(UC).However,their clinical benefit is limited by inefficient homing to the inflamed colonic mucosa.Improving the migration of BMSCs to sites of intestinal inflammation remains a key challenge in the development of cell-based treatments for UC.Tongxie Yaofang(TXYF),a traditional Chinese medicine formula,has been shown to relieve symptoms in UC patients.Our previous in vitro studies also showed that TXYF enhances the migratory capacity of BMSCs.However,whether TXYF enhances the therapeutic effect of BMSCs transplantation in UC,and the mechanisms involved,remain unclear.AIM To determine whether TXYF promotes the homing of BMSCs and improves experimental colitis,and to explore the underlying mechanisms.METHODS BMSCs from Sprague-Dawley rats were characterized via flow cytometry,and TXYF’s effects on migration were evaluated using scratch and Transwell assays.In a colitis model,the synergistic efficacy of TXYF and BMSCs was assessed through disease activity index,histology,immunohistochemistry,tracing,reverse transcriptionquantitative polymerase chain reaction,and western blotting.Furthermore,the stromal cell-derived factor 1(SDF-1)/C-X-C chemokine receptor type 4(CXCR4)axis was investigated using specific antagonists to elucidate the molecular mechanisms of this combinatorial therapy.RESULTS TXYF promoted the in vitro migration of BMSCs.In vivo,the combination of TXYF with BMSCs transplantation alleviated colitis symptoms in rats,improving inflammatory responses,colonic tissue damage,and mucosal barrier function.Our findings suggest that TXYF may enhance the migratory capacity of BMSCs by modulating the SDF-1/CXCR4 axis,thereby increasing their homing to the colonic mucosa.CONCLUSION This study demonstrates that TXYF can enhance the homing efficiency of exogenous BMSCs to the colonic mucosa,likely through the SDF-1/CXCR4 axis,which contributes to the mitigation of experimental colitis.
基金Supported by Natural Science Foundation of Zhejiang Province,No.LY23H050005Zhejiang Medical Technology Project,No.2020KY439,No.2022RC009,No.2024KY645,and No.2024KY697.
摘要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.