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
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
Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal ste...Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal stem cells(MSCs)have shown great promise in tissue regeneration for DKD treatment and have protective effects against DKD,including decreased blood glucose and urinary protein levels and improved renal function.MSCs can directly differ-entiate into kidney cells or act via paracrine mechanisms to reduce apoptosis in DKD by modulating signaling pathways.MSC-derived extracellular vesicles(MSC-EVs)mitigate apoptosis and DKD-related symptoms by transferring miRNAs to target cells or organs.However,studies on the regulatory mechanisms of MSCs and MSC-EVs in apoptosis in DKD are insufficient.This review compre-hensively examines the mechanisms of apoptosis in DKD and research progress regarding the roles of MSCs and MSC-EVs in the disease process.展开更多
CD47 is a ubiquitous and pleiotropic cell-surface receptor.Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries.In a murine closed-fracture model,CD47-nu...CD47 is a ubiquitous and pleiotropic cell-surface receptor.Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries.In a murine closed-fracture model,CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology.To understand the cellular basis for this phenotype,mesenchymal progenitors(MSC)were harvested from bone marrow.CD47-null MSC showed decreased large fibroblast colony formation(CFU-F),significantly less proliferation,and fewer cells in Sphase,although osteoblast differentiation was unaffected.However,consistent with prior research,CD47-null endothelial cells showed increased proliferation relative to WT cells.Similarly,in a murine ischemic fracture model,CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture.Consistent with our in vitro results,in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice,while staining for CD31 and endomucin demonstrated increased endothelial cell density.Finally,WT mice with ischemic fracture that were administered a CD47 morpholino,which blocks CD47 protein production,showed a callus phenotype similar to that of ischemic fractures in CD47-null mice,suggesting the phenotype was not due to developmental changes in the knockout mice.Thus,inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing,in part,by decreasing MSC proliferation.Furthermore,the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.展开更多
Exosomes(Exos)are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication.They play a pivotal role in the pathogenesis and progression of various diseases and offer promi...Exosomes(Exos)are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication.They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions.Exos derived from mesenchymal stem cells(MSCs)have significant immunomodulatory properties.They effectively regulate immune responses by modulating both innate and adaptive immunity.These Exos can inhibit excessive inflammatory responses and promote tissue repair.Moreover,they participate in antigen presentation,which is essential for activating immune responses.The cargo of these Exos,including ligands,proteins,and microRNAs,can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response.By inhibiting lymphocyte proliferation,acting on macrophages,and increasing the population of regulatory T cells,these Exos contribute to maintaining immune and metabolic homeostasis.Furthermore,they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells,which holds potential for immunotherapy applications.Given the immense therapeutic potential of MSC-derived Exos,this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control,tumor suppression,and autoimmune disease management.This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos,offering theoretical references for their future clinical utilization as cell-free drug preparations.展开更多
Dry eye disease(DED)is a multifactorial disorder that disturbs ocular surface equilibrium,considerably diminishing quality of life.Present therapies only offer symptomatic alleviation.Stem cell treatment,especially me...Dry eye disease(DED)is a multifactorial disorder that disturbs ocular surface equilibrium,considerably diminishing quality of life.Present therapies only offer symptomatic alleviation.Stem cell treatment,especially mesenchymal stem cells(MSCs),has surfaced as a viable approach for tissue regeneration and immunological regulation in DED.Preclinical and early clinical investigations indicate that MSCs can improve lacrimal gland functionality,diminish inflammation,and facilitate corneal regeneration.Nonetheless,obstacles persist in enhancing MSC viability,determining the optimal MSC source,and guaranteeing sustained therapeutic effectiveness.Additional extensive randomized clinical trials are required to confirm the efficacy of MSC-based therapies for severe DED.展开更多
Autologous bone marrow-derived mesenchymal stem cells(BMSCs)have been shown to promote osteogenesis;however,the effects of allogeneic BMSCs(allo-BMSCs)on bone regeneration remain unclear.Therefore,we explored the bone...Autologous bone marrow-derived mesenchymal stem cells(BMSCs)have been shown to promote osteogenesis;however,the effects of allogeneic BMSCs(allo-BMSCs)on bone regeneration remain unclear.Therefore,we explored the bone regeneration promotion effect of allo-BMSCs in 3D-printed autologous bone particle(ABP)scaffolds.First,we concurrently printed scaffolds with polycaprolactone,ABPs,and allo-BMSCs for appropriate support,providing bioactive factors and seed cells to promote osteogenesis.In vitro studies showed that ABP scaffolds promoted allo-BMSC osteogenic differentiation.In vivo studies revealed that the implantation of scaffolds loaded with ABPs and allo-BMSCs into canine skull defects for nine months promoted osteogenesis.Further experiments suggested that only a small portion of implanted allo-BMSCs survived and differentiated into vascular endothelial cells,chondrocytes,and osteocytes.The implanted allo-BMSCs released stromal cell-derived factor 1 through paracrine signaling to recruit native BMSCs into the defect,promoting bone regeneration.This study contributes to our understanding of allo-BMSCs,providing information relevant to their future application.展开更多
The global incidence of asthma,a leading respiratory disorder affecting more than 235 million people,has dramatically increased in recent years.Characterized by chronic airway inflammation and an imbalanced response t...The global incidence of asthma,a leading respiratory disorder affecting more than 235 million people,has dramatically increased in recent years.Characterized by chronic airway inflammation and an imbalanced response to airborne irritants,this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea,cough,wheezing,and chest tightness.Conventional asthma therapies,such as corticosteroids,long-actingβ-agonists,and antiinflammatory agents,often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively.These limitations have prompted researchers to explore innovative therapeutic strategies,including stem cell-related interventions,offering hope to those afflicted with this incurable disease.In this review,we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.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
BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchyma...BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchymal stem cells(MSCs)derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors.The mechanism through which MSCs from AS patients achieve this inhibition remains unclear.AIM To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis(AS-MSCs)inhibit osteoclastogenesis.METHODS We analysed fat mass and obesity-associated(FTO)protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase,nuclear factor of activated T cells 1 and cathepsin K.RESULTS We found that FTO,an enzyme responsible for removing methyl groups from RNA,was more abundantly expressed in MSCs from AS patients than in those from healthy donors.Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development.Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage(NORAD)by altering its N6-methyladenosine methylation status.Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284,which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research.CONCLUSION This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.展开更多
BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA ...BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA treatments,their use is limited by the condition itself,and understanding of the underlying mechanisms of OA is lacking.AIM To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.METHODS Sodium iodoacetate was injected into rat articulations to construct an animal model of OA.Interleukin(IL)-1βwas used to induce human chondrocytes(CHON-001)to construct an OA chondrocyte model.Exosomes in hUC-MSCs were isolated using Ribo™Exosome Isolation Reagent.Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins,and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay,terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho-sphate-nick end labelling staining and hematoxylin and eosin staining.RESULTS hUC-MSC-derived exosomes(hUC-MSC-Exos)inhibited the expression of IL-1β-induced inflammatory cytokines,namely,IL-6,IL-8 and tumor necrosis factor-α.hUC-MSC-Exos also improved the viability but inhibited the apoptosis of CHON-001 cells,improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo.Mechanistically,hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p,thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway,alleviating IL-1β-induced chondrocyte inflammation and apoptosis,and ultimately improving the development of OA.CONCLUSION hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway.The present findings suggest that miR-199a-3p delivery by hUC-MSCExos may be a novel strategy for the treatment of OA.展开更多
In this editorial,we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology.They explored an innovative approach to enhancing gemcitabine(GEM)delivery an...In this editorial,we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology.They explored an innovative approach to enhancing gemcitabine(GEM)delivery and efficacy using human bone marrow mesenchymal stem cells(HU-BMSCs)-derived exosomes.The manufacture of GEM-loaded HU-BMSCs-derived exosomes(Exo-GEM)has been optimized.The Tang et al’s study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM,highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer.Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.展开更多
Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with ...Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.Th...BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.There are studies suggesting that stem cell therapy may be effective in the treatment of ASD.AIM To evolve the landscape of ASD treatment,focusing on the potential benefits and safety of stem cell transplantation.METHODS A detailed case report is presented,displaying the positive outcomes observed in a child who underwent intrathecal and intravenous Wharton’s jelly-derived mesenchymal stem cells(WJ-MSCs)transplantation combined with neurorehabilitation.RESULTS The study demonstrates a significant improvement in the child’s functional outcomes(Childhood Autism Rating Scale,Denver 2 Developmental Screening Test),especially in language and gross motor skills.No serious side effects were encountered during the 2-year follow-up.CONCLUSION The findings support the safety and effectiveness of WJ-MSC transplantation in managing ASD.展开更多
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 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 Science and Technology Research Program of Jilin Provincial Department of Education,No.JJKH20231218KJProject of the Jilin Provincial Administration of Traditional Chinese Medicine,No.2024111.
文摘Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal stem cells(MSCs)have shown great promise in tissue regeneration for DKD treatment and have protective effects against DKD,including decreased blood glucose and urinary protein levels and improved renal function.MSCs can directly differ-entiate into kidney cells or act via paracrine mechanisms to reduce apoptosis in DKD by modulating signaling pathways.MSC-derived extracellular vesicles(MSC-EVs)mitigate apoptosis and DKD-related symptoms by transferring miRNAs to target cells or organs.However,studies on the regulatory mechanisms of MSCs and MSC-EVs in apoptosis in DKD are insufficient.This review compre-hensively examines the mechanisms of apoptosis in DKD and research progress regarding the roles of MSCs and MSC-EVs in the disease process.
基金supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)of the National Institutes of Health(NIH)under award numbers F30AR071201(R.L.Z.)and R01 AR066028(K.D.H.)Additional research support is provided by the NIH under a training award T32TR004371(C.A.C.).
文摘CD47 is a ubiquitous and pleiotropic cell-surface receptor.Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries.In a murine closed-fracture model,CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology.To understand the cellular basis for this phenotype,mesenchymal progenitors(MSC)were harvested from bone marrow.CD47-null MSC showed decreased large fibroblast colony formation(CFU-F),significantly less proliferation,and fewer cells in Sphase,although osteoblast differentiation was unaffected.However,consistent with prior research,CD47-null endothelial cells showed increased proliferation relative to WT cells.Similarly,in a murine ischemic fracture model,CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture.Consistent with our in vitro results,in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice,while staining for CD31 and endomucin demonstrated increased endothelial cell density.Finally,WT mice with ischemic fracture that were administered a CD47 morpholino,which blocks CD47 protein production,showed a callus phenotype similar to that of ischemic fractures in CD47-null mice,suggesting the phenotype was not due to developmental changes in the knockout mice.Thus,inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing,in part,by decreasing MSC proliferation.Furthermore,the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.
基金Supported by the National Natural Science Foundation of China,No.82072537the General Project of Hunan Natural Science Foundation,No.2022JJ30412 and No.2021JJ30464.
文摘Exosomes(Exos)are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication.They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions.Exos derived from mesenchymal stem cells(MSCs)have significant immunomodulatory properties.They effectively regulate immune responses by modulating both innate and adaptive immunity.These Exos can inhibit excessive inflammatory responses and promote tissue repair.Moreover,they participate in antigen presentation,which is essential for activating immune responses.The cargo of these Exos,including ligands,proteins,and microRNAs,can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response.By inhibiting lymphocyte proliferation,acting on macrophages,and increasing the population of regulatory T cells,these Exos contribute to maintaining immune and metabolic homeostasis.Furthermore,they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells,which holds potential for immunotherapy applications.Given the immense therapeutic potential of MSC-derived Exos,this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control,tumor suppression,and autoimmune disease management.This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos,offering theoretical references for their future clinical utilization as cell-free drug preparations.
文摘Dry eye disease(DED)is a multifactorial disorder that disturbs ocular surface equilibrium,considerably diminishing quality of life.Present therapies only offer symptomatic alleviation.Stem cell treatment,especially mesenchymal stem cells(MSCs),has surfaced as a viable approach for tissue regeneration and immunological regulation in DED.Preclinical and early clinical investigations indicate that MSCs can improve lacrimal gland functionality,diminish inflammation,and facilitate corneal regeneration.Nonetheless,obstacles persist in enhancing MSC viability,determining the optimal MSC source,and guaranteeing sustained therapeutic effectiveness.Additional extensive randomized clinical trials are required to confirm the efficacy of MSC-based therapies for severe DED.
基金supported by the Science and Technology Development Fund of the Fourth Military Medical University(No.2016XB051)the Military Medical Promotion Plan of the Fourth Military Medical University(No.2016TSA-005)+2 种基金the Science and Technology Program of Guangzhou(No.201604040002)the Youth Development Project of Air Force Medical University(No.21QNPY072)the Xijing Hospital Booster Program(No.XJZT24CZ10).
文摘Autologous bone marrow-derived mesenchymal stem cells(BMSCs)have been shown to promote osteogenesis;however,the effects of allogeneic BMSCs(allo-BMSCs)on bone regeneration remain unclear.Therefore,we explored the bone regeneration promotion effect of allo-BMSCs in 3D-printed autologous bone particle(ABP)scaffolds.First,we concurrently printed scaffolds with polycaprolactone,ABPs,and allo-BMSCs for appropriate support,providing bioactive factors and seed cells to promote osteogenesis.In vitro studies showed that ABP scaffolds promoted allo-BMSC osteogenic differentiation.In vivo studies revealed that the implantation of scaffolds loaded with ABPs and allo-BMSCs into canine skull defects for nine months promoted osteogenesis.Further experiments suggested that only a small portion of implanted allo-BMSCs survived and differentiated into vascular endothelial cells,chondrocytes,and osteocytes.The implanted allo-BMSCs released stromal cell-derived factor 1 through paracrine signaling to recruit native BMSCs into the defect,promoting bone regeneration.This study contributes to our understanding of allo-BMSCs,providing information relevant to their future application.
基金the Joint Innovation Project Funds of Huaqiao University,No.2022YX001.
文摘The global incidence of asthma,a leading respiratory disorder affecting more than 235 million people,has dramatically increased in recent years.Characterized by chronic airway inflammation and an imbalanced response to airborne irritants,this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea,cough,wheezing,and chest tightness.Conventional asthma therapies,such as corticosteroids,long-actingβ-agonists,and antiinflammatory agents,often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively.These limitations have prompted researchers to explore innovative therapeutic strategies,including stem cell-related interventions,offering hope to those afflicted with this incurable disease.In this review,we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.
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.
基金Supported by Guangdong Provincial Clinical Research Center for Orthopedic Diseases,No.2023B110001the Excellent Medical Innovation Talent Program of the Eighth Affiliated Hospital of Sun Yat-sen University,No.YXYXCXRC202101+3 种基金the National Natural Science Foundation of China,No.82172349,No.82372372,No.22105229,No.32170708,No.82102530,No.82102541,No.82103098,No.82103909,No.82104182,No.82104350,No.82170427,No.82171291,No.82172215,No.82172385,and No.82302661Guangdong Natural Science Foundation,No.2023A1515010568 and No.2021A1515111057Shenzhen Science and Technology Program,No.JCYJ20220530144201004 and No.RCBS20210609104445097Futian Healthcare Research Project,No.FTWS2022022,No.FTWS2021013,No.FTWS2023072,and No.FTWS2022047.
文摘BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchymal stem cells(MSCs)derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors.The mechanism through which MSCs from AS patients achieve this inhibition remains unclear.AIM To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis(AS-MSCs)inhibit osteoclastogenesis.METHODS We analysed fat mass and obesity-associated(FTO)protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase,nuclear factor of activated T cells 1 and cathepsin K.RESULTS We found that FTO,an enzyme responsible for removing methyl groups from RNA,was more abundantly expressed in MSCs from AS patients than in those from healthy donors.Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development.Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage(NORAD)by altering its N6-methyladenosine methylation status.Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284,which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research.CONCLUSION This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.
基金Supported by Basic Research Plan of Yunnan Province,No.202201AT070059National Natural Science Foundation of China,No.81760407Science and Technology Talent and Platform Plan of Yunnan Provincial Department of Science and Technology,No.202205AC160066.
文摘BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA treatments,their use is limited by the condition itself,and understanding of the underlying mechanisms of OA is lacking.AIM To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.METHODS Sodium iodoacetate was injected into rat articulations to construct an animal model of OA.Interleukin(IL)-1βwas used to induce human chondrocytes(CHON-001)to construct an OA chondrocyte model.Exosomes in hUC-MSCs were isolated using Ribo™Exosome Isolation Reagent.Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins,and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay,terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho-sphate-nick end labelling staining and hematoxylin and eosin staining.RESULTS hUC-MSC-derived exosomes(hUC-MSC-Exos)inhibited the expression of IL-1β-induced inflammatory cytokines,namely,IL-6,IL-8 and tumor necrosis factor-α.hUC-MSC-Exos also improved the viability but inhibited the apoptosis of CHON-001 cells,improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo.Mechanistically,hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p,thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway,alleviating IL-1β-induced chondrocyte inflammation and apoptosis,and ultimately improving the development of OA.CONCLUSION hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway.The present findings suggest that miR-199a-3p delivery by hUC-MSCExos may be a novel strategy for the treatment of OA.
基金Supported by the grants of China Medical University Hospital,No.DMR-112-173 and No.DMR-113-089the grant from Tungs’Taichung Metro Harbor Hospital,No.TTMHH-R1120013.
文摘In this editorial,we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology.They explored an innovative approach to enhancing gemcitabine(GEM)delivery and efficacy using human bone marrow mesenchymal stem cells(HU-BMSCs)-derived exosomes.The manufacture of GEM-loaded HU-BMSCs-derived exosomes(Exo-GEM)has been optimized.The Tang et al’s study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM,highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer.Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.
基金supported by grants from the Spanish Ministry of Health-PNSD(2019-I039 and 2023-I024)(to MP)FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación PID2021-1243590B-I100(to VMM)+2 种基金GVA(CIAICO/2021/203)(to MP)the Primary Addiction Care Research Network(RD21/0009/0005)(to MP)a predoctoral fellowship from the Generalitat Valenciana(ACIF/2021/338)(to CPC).
文摘Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
文摘BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.There are studies suggesting that stem cell therapy may be effective in the treatment of ASD.AIM To evolve the landscape of ASD treatment,focusing on the potential benefits and safety of stem cell transplantation.METHODS A detailed case report is presented,displaying the positive outcomes observed in a child who underwent intrathecal and intravenous Wharton’s jelly-derived mesenchymal stem cells(WJ-MSCs)transplantation combined with neurorehabilitation.RESULTS The study demonstrates a significant improvement in the child’s functional outcomes(Childhood Autism Rating Scale,Denver 2 Developmental Screening Test),especially in language and gross motor skills.No serious side effects were encountered during the 2-year follow-up.CONCLUSION The findings support the safety and effectiveness of WJ-MSC transplantation in managing ASD.
