Objective To investigate the role of iron death in paraquat(PQ)-induced alveolar epithelial mesangialization(EMT).Methods In August 2023,the appropriate PQ staining concentration as well as the intervention concentrat...Objective To investigate the role of iron death in paraquat(PQ)-induced alveolar epithelial mesangialization(EMT).Methods In August 2023,the appropriate PQ staining concentration as well as the intervention concentration of lipoinhibitor-1(Lip-1)were screened by CCK8 method.The RLE-6TN cells were divided into three groups,which were control group,PQ group and iron death inhibition group,200μmol/L PQ solution was given to the PQ group,and PQ 200μmol/L and 0.1μmol/L Lip-1 solution was given to the iron death inhibition group,the control group was added the same amount of cell medium.morphological changess and migratory viability of the cells in each group were observed at 12 h,24 h and 48 h after the poisoning,and the contents of ferrous ions(Fe^(2+)),reactive oxygen radicals(ROS),glutathione(GSH),superoxide dismutase(SOD),and malondialdehyde(MDA)were detected in each group;meanwhile,qRT-PCRRand western-blot were used to determine the molecular expression of E-cadherin,α-smooth muscle actin(α-SMA),and Collagen I in the cells in each group.The difference between group was compared by ANOVA,and the further pairwise comparison was conducted by Bonferroni method.Results Cell viability was detected using CCK8,and the results showed that the cell survival rate of RLE-6TN cells treated with 200μmol/L PQ+0.1μmol/L Lip-1 solution was 56.6%.The migration activity of RLE-6TN cells in the iron death inhibition group was weaker than that in the PQ group after 24 and 48 hours of exposure,and the degree of EMT changes in the cells was reduced compared to the PQ group.After 12,24,and 48 hours of exposure,the Fe^(2+)concentration,ROS fluorescence intensity,and MDA content in the iron death inhibition group decreased compared to the corresponding time points in the PQ group(P<0.05/3),while compared with PQ group,the GSH concentration and SOD concentration increased compared to the corresponding time points in the PQ group(P<0.05/3).The results showed that compared with the control group,the expression levels of E-cadherin mRNA and protein in PQ group and iron death inhibition group were both decreased(P<0.05/3),while compared with PQ group,the expression levels of E-cadherin mRNA and protein in iron death inhibition group were increased(P<0.05/3);Compared with the control group,the expression levels ofα-SMA,Collagen I mRNA and protein in PQ group and iron death inhibition group cells increased(P<0.05/3),while compared with PQ group,the expression levels ofα-SMA,Collagen I mRNA and protein in iron death inhibition group cells decreased(P<0.05/3).Conclusion Ferroptosis is involved in the EMT process of alveolar epithelial cells induced by PQ.Inhibiting ferroptosis can reduce cellular oxidative damage and alleviate the degree of cellular EMT.展开更多
Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microgl...Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.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
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
Ischemic stroke is a significant global health crisis,frequently resulting in disability or death,with limited therapeutic interventions available.Although various intrinsic reparative processes are initiated within t...Ischemic stroke is a significant global health crisis,frequently resulting in disability or death,with limited therapeutic interventions available.Although various intrinsic reparative processes are initiated within the ischemic brain,these mechanisms are often insufficient to restore neuronal functionality.This has led to intensive investigation into the use of exogenous stem cells as a potential therapeutic option.This comprehensive review outlines the ontogeny and mechanisms of activation of endogenous neural stem cells within the adult brain following ischemic events,with focus on the impact of stem cell-based therapies on neural stem cells.Exogenous stem cells have been shown to enhance the proliferation of endogenous neural stem cells via direct cell-tocell contact and through the secretion of growth factors and exosomes.Additionally,implanted stem cells may recruit host stem cells from their niches to the infarct area by establishing so-called“biobridges.”Furthermore,xenogeneic and allogeneic stem cells can modify the microenvironment of the infarcted brain tissue through immunomodulatory and angiogenic effects,thereby supporting endogenous neuroregeneration.Given the convergence of regulatory pathways between exogenous and endogenous stem cells and the necessity for a supportive microenvironment,we discuss three strategies to simultaneously enhance the therapeutic efficacy of both cell types.These approaches include:(1)co-administration of various growth factors and pharmacological agents alongside stem cell transplantation to reduce stem cell apoptosis;(2)synergistic administration of stem cells and their exosomes to amplify paracrine effects;and(3)integration of stem cells within hydrogels,which provide a protective scaffold for the implanted cells while facilitating the regeneration of neural tissue and the reconstitution of neural circuits.This comprehensive review highlights the interactions and shared regulatory mechanisms between endogenous neural stem cells and exogenously implanted stem cells and may offer new insights for improving the efficacy of stem cell-based therapies in the treatment of ischemic stroke.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
Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good m...Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.展开更多
Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in hu...Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in humans remain unclear,including cell viability,distribution,migration,and fate.Conventional cell tracing methods cannot be used in the clinic.The use of superparamagnetic iron oxide nanoparticles as contrast agents allows for the observation of transplanted cells using magnetic resonance imaging.In 2016,the National Medical Products Administration of China approved a new superparamagnetic iron oxide nanoparticle,Ruicun,for use as a contrast agent in clinical trials.In the present study,an acute hemi-transection spinal cord injury model was established in beagle dogs.The injury was then treated by transplantation of Ruicun-labeled mesenchymal stromal cells.The results indicated that Ruicunlabeled mesenchymal stromal cells repaired damaged spinal cord fibers and partially restored neurological function in animals with acute spinal cord injury.T2*-weighted imaging revealed low signal areas on both sides of the injured spinal cord.The results of quantitative susceptibility mapping with ultrashort echo time sequences indicated that Ruicun-labeled mesenchymal stromal cells persisted stably within the injured spinal cord for over 4 weeks.These findings suggest that magnetic resonance imaging has the potential to effectively track the migration of Ruicun-labeled mesenchymal stromal cells and assess their ability to repair spinal cord injury.展开更多
Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells en...Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.展开更多
Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma.Its pathophysiological mechanisms involve primary and secondary injury phases,leading to progressive retinal ganglion cell loss and axonal...Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma.Its pathophysiological mechanisms involve primary and secondary injury phases,leading to progressive retinal ganglion cell loss and axonal degeneration.Contributing factors such as physical trauma,oxidative stress,neuroinflammation,and glial scar formation exacerbate disease progression and retinal ganglion cell death.Multiple forms of cell death—including apoptosis,pyroptosis,necroptosis,and ferroptosis—are involved at different disease stages.Although current treatments,such as corticosteroid therapy and surgical interventions,have limited efficacy,cell-based therapies have emerged as a promising approach that simultaneously promotes neuroprotection and retinal ganglion cell regeneration.This review summarizes recent advances in cell-based therapies for traumatic optic neuropathy.In the context of cell replacement therapy,retinal ganglion cell-like cells derived from embryonic stem cells and induced pluripotent stem cells—via chemical induction or direct reprogramming—have demonstrated the ability to integrate into the host retina and survive for weeks to months,potentially improving visual function.Mesenchymal stem cells derived from various sources,including bone marrow,umbilical cord,placenta,and adipose tissue,have been shown to enhance retinal ganglion cell survival,stimulate axonal regeneration,and support partial functional recovery.Additionally,neural stem/progenitor cells derived from human embryonic stem cells offer neuroprotective effects and function as“neuronal relays,”facilitating reconnection between damaged regions of the optic nerve and the visual pathway.Beyond direct cell transplantation,cell-derived products,such as extracellular vesicles and cell-extracted solutions,have demonstrated promising neuroprotective effects in traumatic optic neuropathy.Despite significant progress,several challenges remain,including limited integration of transplanted cells,suboptimal functional vision recovery,the need for precise timing and delivery methods,and an incomplete understanding of the role of the retinal microenvironment and glial cell activation in neuroprotection and neuroregeneration.Furthermore,studies with longer observation periods and deeper mechanistic insights into the therapeutic effects of cell-based therapies remain scarce.Two Phase I clinical trials have confirmed the safety and potential benefits of cell-based therapy for traumatic optic neuropathy,with reported improvements in visual acuity.However,further studies are needed to validate these findings and establish significant therapeutic outcomes.In conclusion,cell-based therapies hold great promise for treating traumatic optic neuropathy,but critical obstacles must be overcome to achieve functional optic nerve regeneration.Emerging bioengineering strategies,such as scaffold-based transplantation,may improve cell survival and axonal guidance.Successful clinical translation will require rigorous preclinical validation,standardized protocols,and the integration of advanced imaging techniques to optimize therapeutic efficacy.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.展开更多
Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various ne...Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.展开更多
Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery.Therefore,there is an urgent need to develop new methods for the treatment of this condition.E...Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery.Therefore,there is an urgent need to develop new methods for the treatment of this condition.Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions.They have low immunogenicity,good stability,high delivery efficiency,and the ability to cross the blood–brain barrier.These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke.The rapid development of nanotechnology has advanced the application of engineered exosomes,which can effectively improve targeting ability,enhance therapeutic efficacy,and minimize the dosages needed.Advances in technology have also driven clinical translational research on exosomes.In this review,we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke,including their antiinflammation,anti-apoptosis,autophagy-regulation,angiogenesis,neurogenesis,and glial scar formation reduction effects.However,it is worth noting that,despite their significant therapeutic potential,there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes.Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke.Ultimately,our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.展开更多
“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health pro...“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.展开更多
Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to impr...Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.展开更多
Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,ha...Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,has garnered attention for cartilage repair in OA.While the iliac crest is the traditional site for bone marrow harvesting(BMH),associated morbidity has prompted the exploration of alternative sites such as the proximal tibia,distal femur,and proximal humerus.This paper reviews the impact of different harvesting sites on mesenchymal stem cell(MSC)yield,viability,and regenerative potential,emphasizing their relevance in knee OA treatment.The iliac crest consistently offers the highest MSC yield,but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity.The integration of harvesting techniques into existing knee surgeries,such as total knee arthroplasty,provides a less invasive approach while maintaining thera-peutic efficacy.However,variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes.Future directions include large-scale comparative studies,advanced characterization of MSCs,and the development of personalized harvesting strategies.Ultimately,the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA,enhancing their clinical utility and patient outcomes.展开更多
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
The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,...The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.展开更多
Dental mesenchymal stem cells(DMSCs)are pivotal for tooth development and periodontal tissue health and play an important role in tissue engineering and regenerative medicine because of their multidirectional differen...Dental mesenchymal stem cells(DMSCs)are pivotal for tooth development and periodontal tissue health and play an important role in tissue engineering and regenerative medicine because of their multidirectional differentiation potential and self-renewal ability.The cellular microenvironment regulates the fate of stem cells and can be modified using various optimization techniques.These methods can influence the cellular microenvironment,activate disparate signaling pathways,and induce different biological effects.“Epigenetic regulation”refers to the process of influencing gene expression and regulating cell fate without altering DNA sequences,such as histone methylation.Histone methylation modifications regulate pivotal transcription factors governing DMSCs differentiation into osteo-/odontogenic lineages.The most important sites of histone methylation in tooth organization were found to be H3K4,H3K9,and H3K27.Histone methylation affects gene expression and regulates stem cell differentiation by maintaining a delicate balance between major trimethylation sites,generating distinct chromatin structures associated with specific downstream transcriptional states.Several crucial signaling pathways associated with osteogenic differentiation are susceptible to modulation via histone methylation modifications.A deeper understanding of the regulatory mechanisms governing histone methylation modifications in osteo-/odontogenic differentiation and immune-inflammatory responses of DMSCs will facilitate further investigation of the epigenetic regulation of histone methylation in DMSC-mediated tissue regeneration and inflammation.Here is a concise overview of the pivotal functions of epigenetic histone methylation at H3K4,H3K9,and H3K27 in the regulation of osteo-/odontogenic differentiation and renewal of DMSCs in both non-inflammatory and inflammatory microenvironments.This review summarizes the current research on these processes in the context of tissue regeneration and therapeutic interventions.展开更多
Inflammatory bowel disease(IBD)is a persistent gastrointestinal ailment driven by a range of immunological and pathophysiological factors,and often exposes patients to persistent pain and a greater risk of tumor devel...Inflammatory bowel disease(IBD)is a persistent gastrointestinal ailment driven by a range of immunological and pathophysiological factors,and often exposes patients to persistent pain and a greater risk of tumor development.In clinical settings,sulfasalazine is among the most common treatments used to manage IBD,but such treatment can result in a range of side effects in addition to leading to relatively poor efficacy.In certain refractory cases,patients must undergo surgical resection of affected tissues,underscoring the need to devise safer and more efficacious forms of alternative treatment.Mesenchymal stem cells(MSCs)have recently been shown to exhibit been shown to exhibit robust immunomodulatory activity and potential for differentiation such that they may be an effective tool for treating IBD.Acupuncture has also shown promise as an efficacious treatment option for IBD,performing better than drug-based treatments in certain clinical trials.Acupuncture is capable of enhancing endogenous MSC proliferation and homing,enabling these cells to more effectively migrate toward target lesion sites and to promote tissue repair.In light of these findings,this review was formulated to survey the potential therapeutic advantages of combining MSCs and acupuncture when attempting to treat IBD.展开更多
文摘Objective To investigate the role of iron death in paraquat(PQ)-induced alveolar epithelial mesangialization(EMT).Methods In August 2023,the appropriate PQ staining concentration as well as the intervention concentration of lipoinhibitor-1(Lip-1)were screened by CCK8 method.The RLE-6TN cells were divided into three groups,which were control group,PQ group and iron death inhibition group,200μmol/L PQ solution was given to the PQ group,and PQ 200μmol/L and 0.1μmol/L Lip-1 solution was given to the iron death inhibition group,the control group was added the same amount of cell medium.morphological changess and migratory viability of the cells in each group were observed at 12 h,24 h and 48 h after the poisoning,and the contents of ferrous ions(Fe^(2+)),reactive oxygen radicals(ROS),glutathione(GSH),superoxide dismutase(SOD),and malondialdehyde(MDA)were detected in each group;meanwhile,qRT-PCRRand western-blot were used to determine the molecular expression of E-cadherin,α-smooth muscle actin(α-SMA),and Collagen I in the cells in each group.The difference between group was compared by ANOVA,and the further pairwise comparison was conducted by Bonferroni method.Results Cell viability was detected using CCK8,and the results showed that the cell survival rate of RLE-6TN cells treated with 200μmol/L PQ+0.1μmol/L Lip-1 solution was 56.6%.The migration activity of RLE-6TN cells in the iron death inhibition group was weaker than that in the PQ group after 24 and 48 hours of exposure,and the degree of EMT changes in the cells was reduced compared to the PQ group.After 12,24,and 48 hours of exposure,the Fe^(2+)concentration,ROS fluorescence intensity,and MDA content in the iron death inhibition group decreased compared to the corresponding time points in the PQ group(P<0.05/3),while compared with PQ group,the GSH concentration and SOD concentration increased compared to the corresponding time points in the PQ group(P<0.05/3).The results showed that compared with the control group,the expression levels of E-cadherin mRNA and protein in PQ group and iron death inhibition group were both decreased(P<0.05/3),while compared with PQ group,the expression levels of E-cadherin mRNA and protein in iron death inhibition group were increased(P<0.05/3);Compared with the control group,the expression levels ofα-SMA,Collagen I mRNA and protein in PQ group and iron death inhibition group cells increased(P<0.05/3),while compared with PQ group,the expression levels ofα-SMA,Collagen I mRNA and protein in iron death inhibition group cells decreased(P<0.05/3).Conclusion Ferroptosis is involved in the EMT process of alveolar epithelial cells induced by PQ.Inhibiting ferroptosis can reduce cellular oxidative damage and alleviate the degree of cellular EMT.
基金supported by the Natural Science Foundation of Yunnan Province,No.202401AS070086(to ZW)the National Key Research and Development Program of China,No.2018YFA0801403(to ZW)+1 种基金Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(to ZW)the Natural Science Foundation of China,No.31960120(to ZW)。
文摘Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.
文摘Bone regeneration for non-load-bearing defects remains a significant clinical challenge requiring advanced biomaterials and cellular strategies.Adiposederived mesenchymal stem cells(AD-MSCs)have garnered significant interest in bone tissue engineering(BTE)because of their abundant availability,minimally invasive harvesting procedures,and robust differentiation potential into osteogenic lineages.Unlike bone marrow-derived mesenchymal stem cells,AD-MSCs can be easily obtained in large quantities,making them appealing alternatives for therapeutic applications.This review explores hydrogels containing polymers,such as chitosan,collagen,gelatin,and hyaluronic acid,and their composites,tailored for BTE,and emphasizes the importance of these hydrogels as scaffolds for the delivery of AD-MSCs.Various hydrogel fabrication techniques and biocompatibility assessments are discussed,along with innovative modifications to enhance osteogenesis.This review also briefly outlines AD-MSC isolation methods and advanced embedding techniques for precise cell placement,such as direct encapsulation and three-dimensional bioprinting.We discuss the mechanisms of bone regeneration in the AD-MSC-laden hydrogels,including osteoinduction,vascularization,and extracellular matrix remodeling.We also review the preclinical and clinical applications of AD-MSC-hydrogel systems,emphasizing their success and limitations.In this review,we provide a comprehensive overview of AD-MSC-based hydrogel systems to guide the development of effective therapies for bone regeneration.
文摘BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention for its role in influencing their function,accessibility,and readiness for clinical use.AIM To identify the most suitable adipose source for MSC isolation and expansion for further applications.METHODS We isolated MSCs from solid adipose tissue and liposuction aspirates using the enzyme method.The MSCs were examined for their expansion using population doubling time,differentiation capacity using multilineage differentiation induction,surface markers using flow cytometry,and stability of chromosomes using the karyotyping method.Growth factors and cytokines in MSC-conditioned media were analyzed using the Luminex assay.RESULTS MSCs were isolated from solid adipose tissue and lipoaspirates and expanded from passage 0 to passage 2.All adipose-derived MSCs(AD-MSCs)exhibited the typical elongated,spindle-shaped morphology and comparable proliferation rate.They expressed positive surface markers(cluster of differentiation 73[CD73]:>97%,CD90:>98%,and CD105:>95%),and negative markers(<1%).All MSCs expressed similar levels of stemness genes(octamer-binding transcription factor 4,SRY-box 2,Krüppel-like factor,and MYC),colonyforming,and trilineage differentiation potential.Karyotyping analysis revealed normal chromosomal patterns in all samples,except one sample exhibiting a polymorphism(1qh+).Furthermore,the growth factors and cytokines of hepatocyte growth factor,vascular endothelial growth factor A,interleukin 6(IL-6),and IL-8 were detected in all AD-MSC conditioned media;but fibroblast growth factor-2 and keratinocyte growth factor were selectively expressed in conditioned media from solid or lipoaspirate AD-MSCs,respectively.CONCLUSION These findings indicate that AD-MSCs from both adipose sources possess all of the characteristic features of MSCs with source-specific secretome differences,which are suitable for further expansion and various clinical applications.
基金supported by the National Key Research and Development Program of China,No.2018YFA0108602the CAMS Initiative for Innovative Medicine,No.2021-1-I2M-019National High-Level Hospital Clinical Research Funding,No.2022-PUMCH-C-042(all to XB)。
文摘Ischemic stroke is a significant global health crisis,frequently resulting in disability or death,with limited therapeutic interventions available.Although various intrinsic reparative processes are initiated within the ischemic brain,these mechanisms are often insufficient to restore neuronal functionality.This has led to intensive investigation into the use of exogenous stem cells as a potential therapeutic option.This comprehensive review outlines the ontogeny and mechanisms of activation of endogenous neural stem cells within the adult brain following ischemic events,with focus on the impact of stem cell-based therapies on neural stem cells.Exogenous stem cells have been shown to enhance the proliferation of endogenous neural stem cells via direct cell-tocell contact and through the secretion of growth factors and exosomes.Additionally,implanted stem cells may recruit host stem cells from their niches to the infarct area by establishing so-called“biobridges.”Furthermore,xenogeneic and allogeneic stem cells can modify the microenvironment of the infarcted brain tissue through immunomodulatory and angiogenic effects,thereby supporting endogenous neuroregeneration.Given the convergence of regulatory pathways between exogenous and endogenous stem cells and the necessity for a supportive microenvironment,we discuss three strategies to simultaneously enhance the therapeutic efficacy of both cell types.These approaches include:(1)co-administration of various growth factors and pharmacological agents alongside stem cell transplantation to reduce stem cell apoptosis;(2)synergistic administration of stem cells and their exosomes to amplify paracrine effects;and(3)integration of stem cells within hydrogels,which provide a protective scaffold for the implanted cells while facilitating the regeneration of neural tissue and the reconstitution of neural circuits.This comprehensive review highlights the interactions and shared regulatory mechanisms between endogenous neural stem cells and exogenously implanted stem cells and may offer new insights for improving the efficacy of stem cell-based therapies in the treatment of ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.82271132(to YL),82101167(to BB)the Natural Science Foundation of Chongqing,Nos.CSTB2022NSCQ-MSX0020(to BB),cstc2019jcyj-msxmX0473(to FC).
文摘Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.
基金supported by the Medicine-Engineering Interdisciplinary Project of Sun Yat-sen Memorial Hospital,China,No.YXYGRH202203(to YW)Key-Area Research and Development Program of Guangdong Province,China,No.2023B1111050003(to HC)Guangzhou Science and Technology Talent Project of China,No.201909020006(to HC).
文摘Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.
基金supported by the National Key R&D Program of China,Nos.2017YFA0104302(to NG and XM)and 2017YFA0104304(to BW and ZZ)
文摘Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in humans remain unclear,including cell viability,distribution,migration,and fate.Conventional cell tracing methods cannot be used in the clinic.The use of superparamagnetic iron oxide nanoparticles as contrast agents allows for the observation of transplanted cells using magnetic resonance imaging.In 2016,the National Medical Products Administration of China approved a new superparamagnetic iron oxide nanoparticle,Ruicun,for use as a contrast agent in clinical trials.In the present study,an acute hemi-transection spinal cord injury model was established in beagle dogs.The injury was then treated by transplantation of Ruicun-labeled mesenchymal stromal cells.The results indicated that Ruicunlabeled mesenchymal stromal cells repaired damaged spinal cord fibers and partially restored neurological function in animals with acute spinal cord injury.T2*-weighted imaging revealed low signal areas on both sides of the injured spinal cord.The results of quantitative susceptibility mapping with ultrashort echo time sequences indicated that Ruicun-labeled mesenchymal stromal cells persisted stably within the injured spinal cord for over 4 weeks.These findings suggest that magnetic resonance imaging has the potential to effectively track the migration of Ruicun-labeled mesenchymal stromal cells and assess their ability to repair spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.32171356(to YW)Self-Support Research Projects of Shihezi University,No.ZZZC2021105(to WJ)+1 种基金Capital Medical University Natural Science Cultivation Fund,No.PYZ23044(to FQM)Beijing Municipal Natural Science Foundation,No.7244410(to JHD)。
文摘Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.
基金supported by the National Key Research and Development Program of China,No.2022YFA1105502(to PG)the National Natural Science Foundation of China,Nos.82271123(to PG),32200618(to ZT)。
文摘Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma.Its pathophysiological mechanisms involve primary and secondary injury phases,leading to progressive retinal ganglion cell loss and axonal degeneration.Contributing factors such as physical trauma,oxidative stress,neuroinflammation,and glial scar formation exacerbate disease progression and retinal ganglion cell death.Multiple forms of cell death—including apoptosis,pyroptosis,necroptosis,and ferroptosis—are involved at different disease stages.Although current treatments,such as corticosteroid therapy and surgical interventions,have limited efficacy,cell-based therapies have emerged as a promising approach that simultaneously promotes neuroprotection and retinal ganglion cell regeneration.This review summarizes recent advances in cell-based therapies for traumatic optic neuropathy.In the context of cell replacement therapy,retinal ganglion cell-like cells derived from embryonic stem cells and induced pluripotent stem cells—via chemical induction or direct reprogramming—have demonstrated the ability to integrate into the host retina and survive for weeks to months,potentially improving visual function.Mesenchymal stem cells derived from various sources,including bone marrow,umbilical cord,placenta,and adipose tissue,have been shown to enhance retinal ganglion cell survival,stimulate axonal regeneration,and support partial functional recovery.Additionally,neural stem/progenitor cells derived from human embryonic stem cells offer neuroprotective effects and function as“neuronal relays,”facilitating reconnection between damaged regions of the optic nerve and the visual pathway.Beyond direct cell transplantation,cell-derived products,such as extracellular vesicles and cell-extracted solutions,have demonstrated promising neuroprotective effects in traumatic optic neuropathy.Despite significant progress,several challenges remain,including limited integration of transplanted cells,suboptimal functional vision recovery,the need for precise timing and delivery methods,and an incomplete understanding of the role of the retinal microenvironment and glial cell activation in neuroprotection and neuroregeneration.Furthermore,studies with longer observation periods and deeper mechanistic insights into the therapeutic effects of cell-based therapies remain scarce.Two Phase I clinical trials have confirmed the safety and potential benefits of cell-based therapy for traumatic optic neuropathy,with reported improvements in visual acuity.However,further studies are needed to validate these findings and establish significant therapeutic outcomes.In conclusion,cell-based therapies hold great promise for treating traumatic optic neuropathy,but critical obstacles must be overcome to achieve functional optic nerve regeneration.Emerging bioengineering strategies,such as scaffold-based transplantation,may improve cell survival and axonal guidance.Successful clinical translation will require rigorous preclinical validation,standardized protocols,and the integration of advanced imaging techniques to optimize therapeutic efficacy.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
基金supported by the National Natural Science Foundation of China,Nos.82471471(to WJ),82471485(to FY)Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation,No.tzjhjw(to WJ)+1 种基金Shaanxi Key Research and Development Plan Project,No.2023-YBSF-353(to XW)the Joint Fund Project of Innovation Research Institute of Xijing Hospital,No.LHJJ24JH13(to ZS)。
文摘Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.
基金supported by the National Natural Science Foundation of China,Nos.82071291(to YY),82301464(to HM)the Norman Bethune Health Science Center of Jilin University,No.2022JBGS03(to YY)+2 种基金a grant from Department of Science and Technology of Jilin Province,Nos.YDZJ202302CXJD061(to YY),20220303002SF(to YY)a grant from Jilin Provincial Key Laboratory,No.YDZJ202302CXJD017(to YY)Talent Reserve Program of First Hospital of Jilin University,No.JDYYCB-2023002(to ZNG)。
文摘Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery.Therefore,there is an urgent need to develop new methods for the treatment of this condition.Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions.They have low immunogenicity,good stability,high delivery efficiency,and the ability to cross the blood–brain barrier.These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke.The rapid development of nanotechnology has advanced the application of engineered exosomes,which can effectively improve targeting ability,enhance therapeutic efficacy,and minimize the dosages needed.Advances in technology have also driven clinical translational research on exosomes.In this review,we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke,including their antiinflammation,anti-apoptosis,autophagy-regulation,angiogenesis,neurogenesis,and glial scar formation reduction effects.However,it is worth noting that,despite their significant therapeutic potential,there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes.Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke.Ultimately,our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.
基金supported by the Key Research and Development Project of Hubei Province of China,2022BCA028(to HC)。
文摘“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.
基金supported by the Natural Science Fund of Fujian Province,No.2020J011058(to JK)the Project of Fujian Provincial Hospital for High-level Hospital Construction,No.2020HSJJ12(to JK)+1 种基金the Fujian Provincial Finance Department Special Fund,No.(2021)848(to FC)the Fujian Provincial Major Scientific and Technological Special Projects on Health,No.2022ZD01008(to FC).
文摘Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.
文摘Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,has garnered attention for cartilage repair in OA.While the iliac crest is the traditional site for bone marrow harvesting(BMH),associated morbidity has prompted the exploration of alternative sites such as the proximal tibia,distal femur,and proximal humerus.This paper reviews the impact of different harvesting sites on mesenchymal stem cell(MSC)yield,viability,and regenerative potential,emphasizing their relevance in knee OA treatment.The iliac crest consistently offers the highest MSC yield,but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity.The integration of harvesting techniques into existing knee surgeries,such as total knee arthroplasty,provides a less invasive approach while maintaining thera-peutic efficacy.However,variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes.Future directions include large-scale comparative studies,advanced characterization of MSCs,and the development of personalized harvesting strategies.Ultimately,the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA,enhancing their clinical utility and patient outcomes.
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 National Natural Science Foundation of China(grant numbers 82072523 to Zhiyong Hou)Postdoctoral program of Clinical medicine of Hebei Medical University(grant numbers PD2023012 to Sujuan Xu)+2 种基金Excellent postdoctoral research funding project of Hebei Province(grant numbers B2023005011 to Sujuan Xu)The 16th special grant of China Postdoctoral Science Foundation(grant numbers 2023T160182 to Sujuan Xu)Natural Science Foundation of Hebei Province,China(grant numbers H2023206230 to Yingchao Yin,H2024206186 to Sujuan Xu).
文摘The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.
基金supported by grants from the National Key Research and Development Program(2022YFA1104401)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-031 to Z.P.F.)grants from Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(NO.CXTD202204 to Z.P.F.).
文摘Dental mesenchymal stem cells(DMSCs)are pivotal for tooth development and periodontal tissue health and play an important role in tissue engineering and regenerative medicine because of their multidirectional differentiation potential and self-renewal ability.The cellular microenvironment regulates the fate of stem cells and can be modified using various optimization techniques.These methods can influence the cellular microenvironment,activate disparate signaling pathways,and induce different biological effects.“Epigenetic regulation”refers to the process of influencing gene expression and regulating cell fate without altering DNA sequences,such as histone methylation.Histone methylation modifications regulate pivotal transcription factors governing DMSCs differentiation into osteo-/odontogenic lineages.The most important sites of histone methylation in tooth organization were found to be H3K4,H3K9,and H3K27.Histone methylation affects gene expression and regulates stem cell differentiation by maintaining a delicate balance between major trimethylation sites,generating distinct chromatin structures associated with specific downstream transcriptional states.Several crucial signaling pathways associated with osteogenic differentiation are susceptible to modulation via histone methylation modifications.A deeper understanding of the regulatory mechanisms governing histone methylation modifications in osteo-/odontogenic differentiation and immune-inflammatory responses of DMSCs will facilitate further investigation of the epigenetic regulation of histone methylation in DMSC-mediated tissue regeneration and inflammation.Here is a concise overview of the pivotal functions of epigenetic histone methylation at H3K4,H3K9,and H3K27 in the regulation of osteo-/odontogenic differentiation and renewal of DMSCs in both non-inflammatory and inflammatory microenvironments.This review summarizes the current research on these processes in the context of tissue regeneration and therapeutic interventions.
基金Supported by the National Natural Science Foundation of China,No.82174524.
文摘Inflammatory bowel disease(IBD)is a persistent gastrointestinal ailment driven by a range of immunological and pathophysiological factors,and often exposes patients to persistent pain and a greater risk of tumor development.In clinical settings,sulfasalazine is among the most common treatments used to manage IBD,but such treatment can result in a range of side effects in addition to leading to relatively poor efficacy.In certain refractory cases,patients must undergo surgical resection of affected tissues,underscoring the need to devise safer and more efficacious forms of alternative treatment.Mesenchymal stem cells(MSCs)have recently been shown to exhibit been shown to exhibit robust immunomodulatory activity and potential for differentiation such that they may be an effective tool for treating IBD.Acupuncture has also shown promise as an efficacious treatment option for IBD,performing better than drug-based treatments in certain clinical trials.Acupuncture is capable of enhancing endogenous MSC proliferation and homing,enabling these cells to more effectively migrate toward target lesion sites and to promote tissue repair.In light of these findings,this review was formulated to survey the potential therapeutic advantages of combining MSCs and acupuncture when attempting to treat IBD.
