Stem cells nanotechnology has emerged as a new exciting area,and holds great potential for research and development of stem cells as novel therapeutic platforms for genetic,traumatic,and degenerative medicine.Vital to...Stem cells nanotechnology has emerged as a new exciting area,and holds great potential for research and development of stem cells as novel therapeutic platforms for genetic,traumatic,and degenerative medicine.Vital to the success of this technology are approaches that reproducibly facilitate in vivo cell tracking,expansion,differentiation,and transplantation.Herein we reported the effects of CdSe/ZnS quantum dots covered multi-walled carbon nanotubes(FMNTs)on mice embryonic stem cell line CCE cells.The FMNTs were prepared by plasma surface treatment and characterized by high resolution transmission electron microscopy(HR-TEM),and incubated with murine ES CCE cells for 1 to 28 day.These ES cells were observed by confocal laser scanning microscopy,and were analyzed by real time reverse transcription-polymerase chain reaction(RT-PCR),flow cytometry(FCM)and MTT method.Results showed that prepared FMNTs exhibited green fluorescent signal,could enter into ES cells-1 in time-dependent means,more than 20µg ml FMNTs induced ES cells become smaller and smaller as the incubation time increased,and inhibited-1 cell growth in dose-and time-dependent means,induced apoptosis of ES cells;conversely,5µg ml FMNTs could markedly stimulate the expression of Sox1 and Hsp27,and inhibit expression of OCT4 in ES cells,FCM analysis showed that differentiation marker Flk-1 exhibited higher expression compared with control ES cells.In conclusion,high dose of FMNTs can inhibit proliferation of ES cells,low dose of FMNTs can improve the differentiation of ES cells,FMNTs can have potential applications in in vivo tracking,imaging and regulation of the proliferation and differentiation of ES cells.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
Bone metastasis is the primary cause of mortality in breast cancer(BC)patients.The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1(DEC1)in promoting BC-related...Bone metastasis is the primary cause of mortality in breast cancer(BC)patients.The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1(DEC1)in promoting BC-related bone metastasis.Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues,with elevated levels correlating with increased metastatic potential,suggesting their synergistic involvement in BC progression.Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells.In MDA-MB-231 cells,DEC1 overexpression(OE)upregulated CXCR4 and proliferation/migration-related genes,whereas DEC1 knockdown reversed these effects.Notably,AMD3100,a specific CXCR4 antagonist,partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes.Mechanistically,DEC1 bound to the CXCR4 promoter region(-230 to-326)and activated its transcription,corroborated by ChIP-seq data.Furthermore,pharmacological inhibition of AKT(LY294002)or JAK2(AZD1480),but not ERK(PD98059),attenuated DEC1-mediated CXCR4 upregulation,although all three inhibitors mitigated DEC1-driven migration-related gene expression.Additionally,DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts,amplifying the CXCR4/CXCL12 axis within the bone microenvironment.Collectively,our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression,providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.展开更多
Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source.Unlike current therapeutic options for patient...Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source.Unlike current therapeutic options for patients,this approach has the potential to provide longterm stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients.The ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain.Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies,the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease.A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024.After screening,76 articles were included in the analysis from which 178 separate transplant studies were identified.From these,graft survival could be assessed in 52 studies and differentiation in 129 studies.Overall,we found that graft survival ranged from<1% to 500% of cells transplanted,with a median of 51%of transplanted cells surviving in the brain;while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%.This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.展开更多
Chicken meat quality directly influences consumer acceptability and is crucial for the economic success of the poultry industry.Genetics and nutrition are key determinants of the meat quality traits in broilers.This r...Chicken meat quality directly influences consumer acceptability and is crucial for the economic success of the poultry industry.Genetics and nutrition are key determinants of the meat quality traits in broilers.This review summarizes the research advances in this field,with a focus on the genetic and nutritional foundations that regulate intramuscular fat(IMF)deposition and meat quality in chickens over the past decade.The effects of embryonic nutrition,both maternal nutrition and in ovo feeding(IOF),on skeletal muscle development,the IMF content,and meat quality traits in broilers are also discussed.In genetics,single-cell RNA sequencing revealed that de novo lipogenesis predominantly occurs in myocytes,which is key to the formation of IMF in chicken muscle tissue.Fatty acid synthase(FASN)is the key enzyme involved in this process.This discovery has reshaped the traditional understanding of intramuscular lipid metabolism in poultry.Key genes,proteins,and pathways,such as FASN,FABP4,PPARG,C/EBPα,SLC27A1;LPL,APOA1,COL1A1;PPAR and ECM–receptor interactions signaling,have been identified to regulate IMF content and distribution by modulating fatty acid metabolism and adipogenesis.LncHLFF was innovatively found to promote ectopic IMF deposition in chickens via exosome-mediated mechanisms without affecting abdominal fat deposition.MiR-27b-3p and miR-128-3p were found to inhibit adipogenic differentiation by targeting PPARG,thereby affecting IMF formation.In nutrition,nutrigenomics research has shown that fructose enhances IMF deposition by activating ChREBP,providing new targets for nutritional interventions.Adjusting dietary components,including energy,protein,amino acids,fatty acids,and phytochemicals(e.g.,rutin),has been shown to significantly improve meat quality in broilers.Maternal nutrition(e.g.,intake of energy,amino acids,vitamins,and trace elements)and IOF(e.g.,N-carbamylglutamate)have also been confirmed to significantly impact offspring meat quality,opening new avenues for improving embryonic nutrition.Based on these significant advancements,this review proposes strategies that integrate genetic and nutritional approaches.These strategies aim to modulate the differentiation fate of paraxial mesenchymal stem cells toward myogenic or adipogenic lineages and the interaction between muscle and adipose tissues.These insights would help to improve meat quality while ensuring the growth performance of broiler chickens.展开更多
Spermatozoa have a highly complex RNA profile.Several of these transcripts are suggested as biomarkers for male infertility and contribute to early development.To analyze the differences between sperm RNA quantity and...Spermatozoa have a highly complex RNA profile.Several of these transcripts are suggested as biomarkers for male infertility and contribute to early development.To analyze the differences between sperm RNA quantity and expression of protamine(PRM1 and PRM2)and testis-specific histone 2B(TH2B)genes,spermatozoa from 33 patients who enrolled in assisted reproduction treatment(ART)program were analyzed.Sperm RNA of teratozoospermic(T),oligoteratozoospermic(OT),and normozoospermic(N)samples was extracted,and the differences in transcript levels among the study groups were analyzed by quantitative real-time polymerase chain reaction(qRT-PCR).The correlations of total RNA per spermatozoon and the expression of the transcripts were evaluated in relation to sperm characteristics and preimplantation embryo development.The mean(±standard deviation)RNA amount per spermatozoon was 28.48(±23.03)femtogram in the overall group and was significantly higher in the OT group than that in N and T groups.Total sperm RNA and gene expression of PRM1 and PRM2 genes were related to preimplantation embryo development and developmental arrest.Specific sperm characteristics were correlated with the expressions of PRM1,PRM2,or TH2B genes.We conclude that the sperm RNA amount and composition are important factors and might influence early embryonic development and also differ in different cases of male infertility.展开更多
Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains...Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.展开更多
Background Extracellular vesicles(EVs)regulate cell metabolism and various biological processes by delivering spe-cific proteins and nucleic acids to surrounding cells.We aimed to investigate the effects of the cargo ...Background Extracellular vesicles(EVs)regulate cell metabolism and various biological processes by delivering spe-cific proteins and nucleic acids to surrounding cells.We aimed to investigate the effects of the cargo contained in EVs derived from adipose-derived stem cells(ASCs)on the porcine embryonic development.Methods ASCs were isolated from porcine adipose tissue and characterized using ASC-specific markers via flow cytometry.EVs were subsequently extracted from the conditioned media of the established ASCs.These EVs were added to the in vitro culture environment of porcine embryos to observe qualitative improvements in embryonic development.Furthermore,the proteins within the EVs were analyzed to investigate the underlying mechanisms.Results We observed a higher blastocyst development rate and increased mitochondrial activity in early stage embryos in the ASC-EVs-supplemented group than in the controls(24.8%±0.8%vs.28.6%±1.1%,respectively).The terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assay of blastocysts also revealed signifi-cantly reduced apoptotic cells in the ASC-EVs-supplemented group.Furthermore,through proteomics,we detected the proteins in ASC-EVs and blastocysts from each treatment group.This analysis revealed a higher fraction of pro-teins in the ASC-EVs-supplemented group than in the controls(1,547 vs.1,495,respectively).Gene analysis confirmed that ASC-EVs showed a high expression of tyrosine-protein kinase(SRC),whereas ASC-EVs supplemented blastocysts showed a higher expression of Cyclin-dependent kinase 1(CDK1).SRC is postulated to activate protein kinase B(AKT),which inhibits the forkhead box O signaling pathway and activates CDK1.Subsequently,CDK1 activation influences the cell cycle,thereby affecting in vitro embryonic development.Conclusion ASC-EVs promote mitochondrial activity,which is crucial for the early development of blastocysts and vital in the downregulation of apoptosis.Additionally,ASC-EVs supply SRC to porcine blastocysts,thereby elon-gating the cell cycle.展开更多
Background Early embryo development plays a pivotal role in determining pregnancy outcomes,postnatal development,and lifelong health.Therefore,the strategic selection of functional nutrients to enhance embryo developm...Background Early embryo development plays a pivotal role in determining pregnancy outcomes,postnatal development,and lifelong health.Therefore,the strategic selection of functional nutrients to enhance embryo development is of paramount importance.In this study,we established a stable porcine trophectoderm cell line expressing dual fluorescent reporter genes driven by the CDX2 and TEAD4 gene promoter segments using lentiviral transfection.Results Three amino acid metabolites—kynurenic acid,taurine,and tryptamine—met the minimum z-score criteria of 2.0 for both luciferase and Renilla luciferase activities and were initially identified as potential metabolites for embryo development,with their beneficial effects validated by qPCR.Given that the identified metabolites are closely related to methionine,arginine,and tryptophan,we selected these three amino acids,using lysine as a standard,and employed response surface methodology combined with our high-throughput screening cell model to efficiently screen and optimize amino acid combination conducive to early embryo development.The optimized candidate amino acid system included lysine(1.87 mmol/L),methionine(0.82 mmol/L),tryptophan(0.23 mmol/L),and arginine(3 mmol/L),with the ratio of 1:0.43:0.12:1.60.In vitro experiments confirmed that this amino acid system enhances the expression of key genes involved in early embryonic development and improves in vitro embryo adhesion.Transcriptomic analysis of blastocysts suggested that candidate amino acid system enhances early embryo development by regulating early embryonic cell cycle and differentiation,as well as improving nutrient absorption.Furthermore,based on response surface methodology,400 sows were used to verify this amino acid system,substituting arginine with the more cost-effective N-carbamoyl glutamate(NCG),a precursor of arginine.The optimal dietary amino acid requirement was predicted to be 0.71%lysine,0.32%methionine,0.22%tryptophan,and 0.10%NCG for sows during early gestation.The optimized amino acid system ratio of the feed,derived from the peripheral release of essential amino acids,was found to be 1:0.45:0.13,which is largely consistent with the results obtained from the cell model optimization.Subsequently,we furtherly verified that this optimal dietary amino acid system significantly increased total litter size,live litter size and litter weight in sows.Conclusions In summary,we successfully established a dual-fluorescent high-throughput screening cell model for the efficient identification of potential nutrients that would promote embryo development and implantation.This innovative approach overcomes the limitations of traditional amino acid nutrition studies in sows,providing a more effective model for enhancing reproductive outcomes.展开更多
In vitro fertilization(IVF)is one of the most used assisted reproductive technology(ART)techniques today.However,the success of IVF procedures heavily relies on maintaining a sterile environment in laboratories.This n...In vitro fertilization(IVF)is one of the most used assisted reproductive technology(ART)techniques today.However,the success of IVF procedures heavily relies on maintaining a sterile environment in laboratories.This narrative review examines the effects of microbiological contamination in IVF laboratories,exploring its sources,impacts on IVF outcomes,and preventive measures.We conducted a complete literature search using databases such as PubMed and Google Scholar,focusing on studies published within the last fifteen years.Our findings highlight that microbiological contamination can significantly impair embryo quality,reduce implantation and pregnancy rates,and increase the risk of miscarriage and infection.The review also discusses current best practices for contamination prevention and identifies areas for future research.This work emphasizes the critical importance of stringent sterility protocols in IVF laboratories and calls for continued vigilance and innovation in maintaining optimal conditions for assisted reproduction.展开更多
Spatial transcriptomics technology provides novel insights into the spatial organization of gene expression during embryonic development.In this study,we propose a method that integrates analysis across both temporal ...Spatial transcriptomics technology provides novel insights into the spatial organization of gene expression during embryonic development.In this study,we propose a method that integrates analysis across both temporal and spatial dimensions to investigate spatial transcriptomics data from mouse embryos at different developmental stages.We quantified the spatial expression pattern of each gene at various stages by calculating its Moran’s I.Furthermore,by employing time-series clustering to identify dynamic co-expression modules,we identified several developmentally stage-specific regulatory gene modules.A key finding was the presence of distinct,stage-specific gene network modules across different developmental periods:Early modules focused on morphogenesis,mid-stage on organ development,and late-stage on neural and tissue maturation.Functional enrichment analysis further confirmed the core biological functions of each module.The dynamic,spatially-resolved gene expression model constructed in this study not only provides new biological insights into the programmed spatiotemporal reorganization of gene regulatory networks during embryonic development but also presents an effective approach for analyzing complex spatiotemporal omics data.This work provides a new perspective for understanding developmental biology,regenerative medicine,and related fields.展开更多
The oviduct epithelium is the initial maternal contact site for embryos after fertilization,offering the microenviron-ment before implantation.This early gestation period is particularly sensitive to stress,which can ...The oviduct epithelium is the initial maternal contact site for embryos after fertilization,offering the microenviron-ment before implantation.This early gestation period is particularly sensitive to stress,which can cause reduced fertil-ity and reproductive disorders in mammals.Nevertheless,the local impact of elevated stress hormones on the ovi-duct epithelium has received limited attention to date,except for a few reports on polyovulatory species like mice and pigs.In this study,we focused on the effects of chronic maternal stress on cattle,given its association with infertil-ity issues in this monoovulatory species.Bovine oviduct epithelial cells(BOEC)differentiated at the air–liquid interface(ALI)were stimulated with 250 nmol/L cortisol for 1 or 3 weeks.Subsequently,they were assessed for morphology,bioelectrical properties,and gene expression related to oviduct function,glucocorticoid pathway,cortisol metabo-lism,inflammation,and apoptosis.Results revealed adverse effects of cortisol on epithelium structure,featured by deciliation,vacuole formation,and multilayering.Additionally,cortisol exposure led to an increase in transepithelial potential difference,downregulated mRNA expression of the major glucocorticoid receptor(NR3C1),upregulated the expression of cortisol-responsive genes(FKBP5,TSC22D3),and significant downregulation of oviductal glycopro-tein 1(OVGP1)and steroid receptors PGR and ESR1.The systematic comparison to a similar experiment previously performed by us in porcine oviduct epithelial cells,indicated that bovine cultures were more susceptible to elevated cortisol levels than porcine.The distinct responses between both species are likely linked to their divergence in the cortisol-induced expression changes of HSD11B2,an enzyme controlling the cellular capacity to metabolise cortisol.These findings provide insights into the species-specific reactions and reproductive consequences triggered by maternal stress.展开更多
Microglia have been recognized as a unique cell population in the central nervous system(CNS)for more than a century[1].However,it was not until 2010 that their developmental origin was clarified.Rather than arising f...Microglia have been recognized as a unique cell population in the central nervous system(CNS)for more than a century[1].However,it was not until 2010 that their developmental origin was clarified.Rather than arising from the neuroectoderm,microglia are derived from erythromyeloid progenitors in the embryonic yolk sac[2].展开更多
Human cytomegalovirus(HCMV)poses a significant risk of neural damage during pregnancy.As the most prevalent intrauterine infectious agent in low-and middle-income countries,HCMV disrupts the development of neural stem...Human cytomegalovirus(HCMV)poses a significant risk of neural damage during pregnancy.As the most prevalent intrauterine infectious agent in low-and middle-income countries,HCMV disrupts the development of neural stem cells,leading to fetal malformations and abnormal structural and physiological functions in the fetal brain.This review summarizes the current understanding of how HCMV infection dysregulates the Wnt signaling pathway to induce fetal malformations and discusses current management strategies.展开更多
Introduction:Hearing loss,particularly congenital hearing loss,poses significant challenges to affected individuals and their families.Recent advancements in regenerative medicine have fueled interest in stem cell the...Introduction:Hearing loss,particularly congenital hearing loss,poses significant challenges to affected individuals and their families.Recent advancements in regenerative medicine have fueled interest in stem cell therapy as a potential solution for hearing restoration.This review discusses the feasibility of using stem cells to regenerate damaged cochlear structures and auditory neurons,focusing on their differentiation potential and integration into the cochlear environment.Discussion:Congenital hearing loss remains a significant global health challenge,with genetic mutations and syndromic conditions contributing to its high prevalence.Advances in regenerative medicine have led to increased interest in stem cell therapy as a potential solution for auditory restoration.Research on embryonic stem cells(ESCs),induced pluripotent stem cells(i PSCs),and mesenchymal stem cells(MSCs)has demonstrated their ability to differentiate into auditory cell types,offering a potential avenue for cochlear regeneration.Gene therapies also present a promising approach for addressing hereditary hearing loss by targeting specific genetic mutations.i PSCs in particular show promise,especially when combined with gene therapy for hereditary hearing loss.Despite encouraging preclinical findings,persistent hurdles remain:immune rejection,limited cell survival,difficulty with cochlear integration,and complex ethical and regulatory considerations.Addressing these barriers is crucial for safe and effective translation into clinical care.In Pakistan,there is a critical need to promote advancements in this field.Positioning Pakistan as an illustrative case within broader low-and middle-income country(LMIC)disparities underscores how limited infrastructure,funding gaps,and weak regulatory frameworks constrain progress and highlight opportunities for regional collaboration.Conclusion:As stem cell research advances,it is crucial to address ethical and regulatory considerations to ensure the responsible translation of these therapies into clinical practice.By integrating stem cell therapy with gene editing techniques and biomaterial scaffolding,the future of regenerative treatment for congenital hearing loss holds transformative potential.展开更多
Following the publication of Xu et al.(2022),an error was identified in Figure 1D.Specifically,the top left panel was inadvertently duplicated during figure preparation.To ensure the accuracy and integrity of our publ...Following the publication of Xu et al.(2022),an error was identified in Figure 1D.Specifically,the top left panel was inadvertently duplicated during figure preparation.To ensure the accuracy and integrity of our published work,we request the publication of a corrigendum with the corrected image.We apologize for this oversight and any confusion it may have caused.The amended figure is provided in the updated Supplementary Materials.展开更多
In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels...In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels at CGIs remains largely elusive.KDM2 proteins(KDM2A and KDM2B)are H3K36me2 demethylases known to bind specifically at CGIs.Here,we report that depletion of each or both KDM2 proteins,or mutation of all their JmjC domains that harbor the H3K36me2 demethylation activity,leads to an increase in DNA methylation at selective CGIs.The Kdm2a/2b double knockout shows a stronger increase in DNA methylation compared with the single mutant of Kdm2a or Kdm2b,indicating that KDM2A and KDM2B redundantly regulate DNA methylation at CGIs.In addition,the increase of CGI DNA methylation upon mutations of KDM2 proteins is associated with the chromatin environment.Our findings reveal that KDM2A and KDM2B function redundantly in regulating DNA methylation at a subset of CGIs in an H3K36me2 demethylation-dependent manner.展开更多
Periodontitis is a common oral disease caused by bacteria coupled with an excessive host immune response.Stem cell therapy can be a promising treatment strategy for periodontitis,but the relevant mechanism is complica...Periodontitis is a common oral disease caused by bacteria coupled with an excessive host immune response.Stem cell therapy can be a promising treatment strategy for periodontitis,but the relevant mechanism is complicated.This study aimed to explore the therapeutic potential of mitochondria from human embryonic stem cell-derived mesenchymal stem cells(hESC-MSCs)for the treatment of periodontitis.The gingival tissues of periodontitis patients are characterized by abnormal mitochondrial structure.Human gingival fibroblasts(HGFs)were exposed to 5μg/mL lipopolysaccharide(LPS)for 24 h to establish a cell injury model.When treated with hESC-MSCs or mitochondria derived from hESC-MSCs,HGFs showed reduced expression of inflammatory genes,increased adenosine triphosphate(ATP)level,decreased reactive oxygen species(ROS)production,and enhanced mitochondrial function compared to the control.The average efficiency of isolated mitochondrial transfer by hESC-MSCs was determined to be 8.93%.Besides,a therapy of local mitochondrial injection in mice with LPS-induced periodontitis showed a reduction in inflammatory gene expression,as well as an increase in both the mitochondrial number and the aspect ratio in gingival tissues.In conclusion,our results indicate that mitochondria derived from hESC-MSCs can reduce the inflammatory response and improve mitochondrial function in HGFs,suggesting that the transfer of mitochondria between hESC-MSCs and HGFs serves as a potential mechanism underlying the therapeutic effect of stem cells.展开更多
Background:Radiofrequency ablation(RFA)is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality.Understanding the biological process related with RFA treatment ...Background:Radiofrequency ablation(RFA)is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality.Understanding the biological process related with RFA treatment is important for improving treatment strategy.This study aimed to identify the critical targets for regulating the efficacy of RFA.Methods:The RFA treatment in hepatocellular carcinoma(HCC)tumor models in vivo,was analyzed by RNA sequencing technology.The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells.Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase(MELK).Results:It was found that RFA treatment upregulated MELK expression,and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response,including anti-tumoral macrophage polarization and increased CD8+T cell cytotoxicity in HCC.Mechanically,MELK binds to fatty acid-binding protein 5(FABP5),and affects its ubiquitination through the K48R pathway to increase its stability,thereby activating protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling axis to weaken the RFA-mediated antitumor effect.In addition,the synthesis of arginylglycylaspartic acid(RGD)-lipid nanoparticles(LNPs)targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC.Conclusions:MELK is a therapeutic target by regulating RFA efficacy in HCC,and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer.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
基金supported by a grant from Strategic Fund for Establishing the International HQs of Universities in Waseda University,Chinese 973 Project(2010CB933901)863 Key Project(2007AA022004)+2 种基金New Century Excellent Talent of Ministry of Education of China(NCET-08-0350)Special Infection Diseases Key Project of China(2009ZX10004-311)Shanghai Science and Technology Fund(10XD1406100 and 1052nm04100)。
文摘Stem cells nanotechnology has emerged as a new exciting area,and holds great potential for research and development of stem cells as novel therapeutic platforms for genetic,traumatic,and degenerative medicine.Vital to the success of this technology are approaches that reproducibly facilitate in vivo cell tracking,expansion,differentiation,and transplantation.Herein we reported the effects of CdSe/ZnS quantum dots covered multi-walled carbon nanotubes(FMNTs)on mice embryonic stem cell line CCE cells.The FMNTs were prepared by plasma surface treatment and characterized by high resolution transmission electron microscopy(HR-TEM),and incubated with murine ES CCE cells for 1 to 28 day.These ES cells were observed by confocal laser scanning microscopy,and were analyzed by real time reverse transcription-polymerase chain reaction(RT-PCR),flow cytometry(FCM)and MTT method.Results showed that prepared FMNTs exhibited green fluorescent signal,could enter into ES cells-1 in time-dependent means,more than 20µg ml FMNTs induced ES cells become smaller and smaller as the incubation time increased,and inhibited-1 cell growth in dose-and time-dependent means,induced apoptosis of ES cells;conversely,5µg ml FMNTs could markedly stimulate the expression of Sox1 and Hsp27,and inhibit expression of OCT4 in ES cells,FCM analysis showed that differentiation marker Flk-1 exhibited higher expression compared with control ES cells.In conclusion,high dose of FMNTs can inhibit proliferation of ES cells,low dose of FMNTs can improve the differentiation of ES cells,FMNTs can have potential applications in in vivo tracking,imaging and regulation of the proliferation and differentiation of ES cells.
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 China(Grant Nos.82073934,81872937)Office of Jiangsu Provincial Academic Degrees Committee(Grant No.JX10114120).
文摘Bone metastasis is the primary cause of mortality in breast cancer(BC)patients.The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1(DEC1)in promoting BC-related bone metastasis.Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues,with elevated levels correlating with increased metastatic potential,suggesting their synergistic involvement in BC progression.Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells.In MDA-MB-231 cells,DEC1 overexpression(OE)upregulated CXCR4 and proliferation/migration-related genes,whereas DEC1 knockdown reversed these effects.Notably,AMD3100,a specific CXCR4 antagonist,partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes.Mechanistically,DEC1 bound to the CXCR4 promoter region(-230 to-326)and activated its transcription,corroborated by ChIP-seq data.Furthermore,pharmacological inhibition of AKT(LY294002)or JAK2(AZD1480),but not ERK(PD98059),attenuated DEC1-mediated CXCR4 upregulation,although all three inhibitors mitigated DEC1-driven migration-related gene expression.Additionally,DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts,amplifying the CXCR4/CXCL12 axis within the bone microenvironment.Collectively,our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression,providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.
基金supported by research grants from the Michael J Fox Foundation for Parkinson’s Research(grant numbers:17244 and 023410)Science Foundation Ireland(Grant Numbers:19/FFP/6554)(to ED)。
文摘Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source.Unlike current therapeutic options for patients,this approach has the potential to provide longterm stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients.The ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain.Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies,the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease.A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024.After screening,76 articles were included in the analysis from which 178 separate transplant studies were identified.From these,graft survival could be assessed in 52 studies and differentiation in 129 studies.Overall,we found that graft survival ranged from<1% to 500% of cells transplanted,with a median of 51%of transplanted cells surviving in the brain;while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%.This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.
基金funded by the Regional Innovation and Development Joint Fund of National Natural Science Foundation of China(Project No.U21A20253)2115 Talent Development Program of China Agricultural University.
文摘Chicken meat quality directly influences consumer acceptability and is crucial for the economic success of the poultry industry.Genetics and nutrition are key determinants of the meat quality traits in broilers.This review summarizes the research advances in this field,with a focus on the genetic and nutritional foundations that regulate intramuscular fat(IMF)deposition and meat quality in chickens over the past decade.The effects of embryonic nutrition,both maternal nutrition and in ovo feeding(IOF),on skeletal muscle development,the IMF content,and meat quality traits in broilers are also discussed.In genetics,single-cell RNA sequencing revealed that de novo lipogenesis predominantly occurs in myocytes,which is key to the formation of IMF in chicken muscle tissue.Fatty acid synthase(FASN)is the key enzyme involved in this process.This discovery has reshaped the traditional understanding of intramuscular lipid metabolism in poultry.Key genes,proteins,and pathways,such as FASN,FABP4,PPARG,C/EBPα,SLC27A1;LPL,APOA1,COL1A1;PPAR and ECM–receptor interactions signaling,have been identified to regulate IMF content and distribution by modulating fatty acid metabolism and adipogenesis.LncHLFF was innovatively found to promote ectopic IMF deposition in chickens via exosome-mediated mechanisms without affecting abdominal fat deposition.MiR-27b-3p and miR-128-3p were found to inhibit adipogenic differentiation by targeting PPARG,thereby affecting IMF formation.In nutrition,nutrigenomics research has shown that fructose enhances IMF deposition by activating ChREBP,providing new targets for nutritional interventions.Adjusting dietary components,including energy,protein,amino acids,fatty acids,and phytochemicals(e.g.,rutin),has been shown to significantly improve meat quality in broilers.Maternal nutrition(e.g.,intake of energy,amino acids,vitamins,and trace elements)and IOF(e.g.,N-carbamylglutamate)have also been confirmed to significantly impact offspring meat quality,opening new avenues for improving embryonic nutrition.Based on these significant advancements,this review proposes strategies that integrate genetic and nutritional approaches.These strategies aim to modulate the differentiation fate of paraxial mesenchymal stem cells toward myogenic or adipogenic lineages and the interaction between muscle and adipose tissues.These insights would help to improve meat quality while ensuring the growth performance of broiler chickens.
基金supported by the Scientific Research Projects Coordination Unit of Istanbul University(No.13930).
文摘Spermatozoa have a highly complex RNA profile.Several of these transcripts are suggested as biomarkers for male infertility and contribute to early development.To analyze the differences between sperm RNA quantity and expression of protamine(PRM1 and PRM2)and testis-specific histone 2B(TH2B)genes,spermatozoa from 33 patients who enrolled in assisted reproduction treatment(ART)program were analyzed.Sperm RNA of teratozoospermic(T),oligoteratozoospermic(OT),and normozoospermic(N)samples was extracted,and the differences in transcript levels among the study groups were analyzed by quantitative real-time polymerase chain reaction(qRT-PCR).The correlations of total RNA per spermatozoon and the expression of the transcripts were evaluated in relation to sperm characteristics and preimplantation embryo development.The mean(±standard deviation)RNA amount per spermatozoon was 28.48(±23.03)femtogram in the overall group and was significantly higher in the OT group than that in N and T groups.Total sperm RNA and gene expression of PRM1 and PRM2 genes were related to preimplantation embryo development and developmental arrest.Specific sperm characteristics were correlated with the expressions of PRM1,PRM2,or TH2B genes.We conclude that the sperm RNA amount and composition are important factors and might influence early embryonic development and also differ in different cases of male infertility.
基金supported by the Medical Science Data Center at Shanghai Medical College of Fudan Universitysupported by grants from National Natural Science Foundation of China (81974229and 82171167 to W.F.,82330049 to W.Z.)+2 种基金Xiamen Municipal Major Project of High-Quality Development of Health and Wellness Technology Program (2024-GZL-GD06 to W.F.)National Key R&D Program of China (2022YFA0806603 to W.F.)Science and Technology Program of Guangzhou,China (2024A04J4924 to C.H.)
文摘Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.
基金The Ministry of Science and ICT through the National Research Foundation of Korea (NRF) supported this study (grant numbers:2021R1A2C2009294)The Research Institute for Veterinary Science at the Seoul National University partially funded this study。
文摘Background Extracellular vesicles(EVs)regulate cell metabolism and various biological processes by delivering spe-cific proteins and nucleic acids to surrounding cells.We aimed to investigate the effects of the cargo contained in EVs derived from adipose-derived stem cells(ASCs)on the porcine embryonic development.Methods ASCs were isolated from porcine adipose tissue and characterized using ASC-specific markers via flow cytometry.EVs were subsequently extracted from the conditioned media of the established ASCs.These EVs were added to the in vitro culture environment of porcine embryos to observe qualitative improvements in embryonic development.Furthermore,the proteins within the EVs were analyzed to investigate the underlying mechanisms.Results We observed a higher blastocyst development rate and increased mitochondrial activity in early stage embryos in the ASC-EVs-supplemented group than in the controls(24.8%±0.8%vs.28.6%±1.1%,respectively).The terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assay of blastocysts also revealed signifi-cantly reduced apoptotic cells in the ASC-EVs-supplemented group.Furthermore,through proteomics,we detected the proteins in ASC-EVs and blastocysts from each treatment group.This analysis revealed a higher fraction of pro-teins in the ASC-EVs-supplemented group than in the controls(1,547 vs.1,495,respectively).Gene analysis confirmed that ASC-EVs showed a high expression of tyrosine-protein kinase(SRC),whereas ASC-EVs supplemented blastocysts showed a higher expression of Cyclin-dependent kinase 1(CDK1).SRC is postulated to activate protein kinase B(AKT),which inhibits the forkhead box O signaling pathway and activates CDK1.Subsequently,CDK1 activation influences the cell cycle,thereby affecting in vitro embryonic development.Conclusion ASC-EVs promote mitochondrial activity,which is crucial for the early development of blastocysts and vital in the downregulation of apoptosis.Additionally,ASC-EVs supply SRC to porcine blastocysts,thereby elon-gating the cell cycle.
基金supported by National Natural Science Foundation of China (32172747 and 32425052)
文摘Background Early embryo development plays a pivotal role in determining pregnancy outcomes,postnatal development,and lifelong health.Therefore,the strategic selection of functional nutrients to enhance embryo development is of paramount importance.In this study,we established a stable porcine trophectoderm cell line expressing dual fluorescent reporter genes driven by the CDX2 and TEAD4 gene promoter segments using lentiviral transfection.Results Three amino acid metabolites—kynurenic acid,taurine,and tryptamine—met the minimum z-score criteria of 2.0 for both luciferase and Renilla luciferase activities and were initially identified as potential metabolites for embryo development,with their beneficial effects validated by qPCR.Given that the identified metabolites are closely related to methionine,arginine,and tryptophan,we selected these three amino acids,using lysine as a standard,and employed response surface methodology combined with our high-throughput screening cell model to efficiently screen and optimize amino acid combination conducive to early embryo development.The optimized candidate amino acid system included lysine(1.87 mmol/L),methionine(0.82 mmol/L),tryptophan(0.23 mmol/L),and arginine(3 mmol/L),with the ratio of 1:0.43:0.12:1.60.In vitro experiments confirmed that this amino acid system enhances the expression of key genes involved in early embryonic development and improves in vitro embryo adhesion.Transcriptomic analysis of blastocysts suggested that candidate amino acid system enhances early embryo development by regulating early embryonic cell cycle and differentiation,as well as improving nutrient absorption.Furthermore,based on response surface methodology,400 sows were used to verify this amino acid system,substituting arginine with the more cost-effective N-carbamoyl glutamate(NCG),a precursor of arginine.The optimal dietary amino acid requirement was predicted to be 0.71%lysine,0.32%methionine,0.22%tryptophan,and 0.10%NCG for sows during early gestation.The optimized amino acid system ratio of the feed,derived from the peripheral release of essential amino acids,was found to be 1:0.45:0.13,which is largely consistent with the results obtained from the cell model optimization.Subsequently,we furtherly verified that this optimal dietary amino acid system significantly increased total litter size,live litter size and litter weight in sows.Conclusions In summary,we successfully established a dual-fluorescent high-throughput screening cell model for the efficient identification of potential nutrients that would promote embryo development and implantation.This innovative approach overcomes the limitations of traditional amino acid nutrition studies in sows,providing a more effective model for enhancing reproductive outcomes.
文摘In vitro fertilization(IVF)is one of the most used assisted reproductive technology(ART)techniques today.However,the success of IVF procedures heavily relies on maintaining a sterile environment in laboratories.This narrative review examines the effects of microbiological contamination in IVF laboratories,exploring its sources,impacts on IVF outcomes,and preventive measures.We conducted a complete literature search using databases such as PubMed and Google Scholar,focusing on studies published within the last fifteen years.Our findings highlight that microbiological contamination can significantly impair embryo quality,reduce implantation and pregnancy rates,and increase the risk of miscarriage and infection.The review also discusses current best practices for contamination prevention and identifies areas for future research.This work emphasizes the critical importance of stringent sterility protocols in IVF laboratories and calls for continued vigilance and innovation in maintaining optimal conditions for assisted reproduction.
基金supported by the National Natural Science Foundation of China(Grant Nos.12090052,U24A2014,and 12325405).
文摘Spatial transcriptomics technology provides novel insights into the spatial organization of gene expression during embryonic development.In this study,we propose a method that integrates analysis across both temporal and spatial dimensions to investigate spatial transcriptomics data from mouse embryos at different developmental stages.We quantified the spatial expression pattern of each gene at various stages by calculating its Moran’s I.Furthermore,by employing time-series clustering to identify dynamic co-expression modules,we identified several developmentally stage-specific regulatory gene modules.A key finding was the presence of distinct,stage-specific gene network modules across different developmental periods:Early modules focused on morphogenesis,mid-stage on organ development,and late-stage on neural and tissue maturation.Functional enrichment analysis further confirmed the core biological functions of each module.The dynamic,spatially-resolved gene expression model constructed in this study not only provides new biological insights into the programmed spatiotemporal reorganization of gene regulatory networks during embryonic development but also presents an effective approach for analyzing complex spatiotemporal omics data.This work provides a new perspective for understanding developmental biology,regenerative medicine,and related fields.
基金German research Foundation(DFG,grant numbers:CH2321/1–1 and SCHO1231/7–1)JH has received a scholarship from the Chinese Scholarship Council(CSC No.:201908350115).
文摘The oviduct epithelium is the initial maternal contact site for embryos after fertilization,offering the microenviron-ment before implantation.This early gestation period is particularly sensitive to stress,which can cause reduced fertil-ity and reproductive disorders in mammals.Nevertheless,the local impact of elevated stress hormones on the ovi-duct epithelium has received limited attention to date,except for a few reports on polyovulatory species like mice and pigs.In this study,we focused on the effects of chronic maternal stress on cattle,given its association with infertil-ity issues in this monoovulatory species.Bovine oviduct epithelial cells(BOEC)differentiated at the air–liquid interface(ALI)were stimulated with 250 nmol/L cortisol for 1 or 3 weeks.Subsequently,they were assessed for morphology,bioelectrical properties,and gene expression related to oviduct function,glucocorticoid pathway,cortisol metabo-lism,inflammation,and apoptosis.Results revealed adverse effects of cortisol on epithelium structure,featured by deciliation,vacuole formation,and multilayering.Additionally,cortisol exposure led to an increase in transepithelial potential difference,downregulated mRNA expression of the major glucocorticoid receptor(NR3C1),upregulated the expression of cortisol-responsive genes(FKBP5,TSC22D3),and significant downregulation of oviductal glycopro-tein 1(OVGP1)and steroid receptors PGR and ESR1.The systematic comparison to a similar experiment previously performed by us in porcine oviduct epithelial cells,indicated that bovine cultures were more susceptible to elevated cortisol levels than porcine.The distinct responses between both species are likely linked to their divergence in the cortisol-induced expression changes of HSD11B2,an enzyme controlling the cellular capacity to metabolise cortisol.These findings provide insights into the species-specific reactions and reproductive consequences triggered by maternal stress.
基金supported in part by National Science and Technology Major Project of National Health Commission of China(2023ZD0520300)the National Natural Science Foundation of China(32130037 and 32370953)the Tsinghua University Initiative Scientific Research Program,SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine and the Research Fund of Vanke School of Public Health,Tsinghua University.H.Q.is a New Cornerstone Investigator.
文摘Microglia have been recognized as a unique cell population in the central nervous system(CNS)for more than a century[1].However,it was not until 2010 that their developmental origin was clarified.Rather than arising from the neuroectoderm,microglia are derived from erythromyeloid progenitors in the embryonic yolk sac[2].
基金supported by the Natural Science Foundation of Shandong Province(ZR2019MC059)the Traditional Chinese Medicine Science Project of Shandong Province(M-2023093)the Weifang Municipal Science and Technology Development Program(2025YX037).
文摘Human cytomegalovirus(HCMV)poses a significant risk of neural damage during pregnancy.As the most prevalent intrauterine infectious agent in low-and middle-income countries,HCMV disrupts the development of neural stem cells,leading to fetal malformations and abnormal structural and physiological functions in the fetal brain.This review summarizes the current understanding of how HCMV infection dysregulates the Wnt signaling pathway to induce fetal malformations and discusses current management strategies.
文摘Introduction:Hearing loss,particularly congenital hearing loss,poses significant challenges to affected individuals and their families.Recent advancements in regenerative medicine have fueled interest in stem cell therapy as a potential solution for hearing restoration.This review discusses the feasibility of using stem cells to regenerate damaged cochlear structures and auditory neurons,focusing on their differentiation potential and integration into the cochlear environment.Discussion:Congenital hearing loss remains a significant global health challenge,with genetic mutations and syndromic conditions contributing to its high prevalence.Advances in regenerative medicine have led to increased interest in stem cell therapy as a potential solution for auditory restoration.Research on embryonic stem cells(ESCs),induced pluripotent stem cells(i PSCs),and mesenchymal stem cells(MSCs)has demonstrated their ability to differentiate into auditory cell types,offering a potential avenue for cochlear regeneration.Gene therapies also present a promising approach for addressing hereditary hearing loss by targeting specific genetic mutations.i PSCs in particular show promise,especially when combined with gene therapy for hereditary hearing loss.Despite encouraging preclinical findings,persistent hurdles remain:immune rejection,limited cell survival,difficulty with cochlear integration,and complex ethical and regulatory considerations.Addressing these barriers is crucial for safe and effective translation into clinical care.In Pakistan,there is a critical need to promote advancements in this field.Positioning Pakistan as an illustrative case within broader low-and middle-income country(LMIC)disparities underscores how limited infrastructure,funding gaps,and weak regulatory frameworks constrain progress and highlight opportunities for regional collaboration.Conclusion:As stem cell research advances,it is crucial to address ethical and regulatory considerations to ensure the responsible translation of these therapies into clinical practice.By integrating stem cell therapy with gene editing techniques and biomaterial scaffolding,the future of regenerative treatment for congenital hearing loss holds transformative potential.
文摘Following the publication of Xu et al.(2022),an error was identified in Figure 1D.Specifically,the top left panel was inadvertently duplicated during figure preparation.To ensure the accuracy and integrity of our published work,we request the publication of a corrigendum with the corrected image.We apologize for this oversight and any confusion it may have caused.The amended figure is provided in the updated Supplementary Materials.
基金supported by the National Natural Science Foundation of China(32070607)the National Key Research and Development Program of China(2020YFA0804000)the CAS Project for Young Scientists in Basic Research(YSBR-012).
文摘In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels at CGIs remains largely elusive.KDM2 proteins(KDM2A and KDM2B)are H3K36me2 demethylases known to bind specifically at CGIs.Here,we report that depletion of each or both KDM2 proteins,or mutation of all their JmjC domains that harbor the H3K36me2 demethylation activity,leads to an increase in DNA methylation at selective CGIs.The Kdm2a/2b double knockout shows a stronger increase in DNA methylation compared with the single mutant of Kdm2a or Kdm2b,indicating that KDM2A and KDM2B redundantly regulate DNA methylation at CGIs.In addition,the increase of CGI DNA methylation upon mutations of KDM2 proteins is associated with the chromatin environment.Our findings reveal that KDM2A and KDM2B function redundantly in regulating DNA methylation at a subset of CGIs in an H3K36me2 demethylation-dependent manner.
基金supported by the Key R&D Program of Zhejiang(No.2023C03072)the Medical and Health Science and Technology Program of Zhejiang Province(No.2021PY007)and the National Key Research and Development Program of China(Nos.2021YFA1301100 and 2021YFA1301101).
文摘Periodontitis is a common oral disease caused by bacteria coupled with an excessive host immune response.Stem cell therapy can be a promising treatment strategy for periodontitis,but the relevant mechanism is complicated.This study aimed to explore the therapeutic potential of mitochondria from human embryonic stem cell-derived mesenchymal stem cells(hESC-MSCs)for the treatment of periodontitis.The gingival tissues of periodontitis patients are characterized by abnormal mitochondrial structure.Human gingival fibroblasts(HGFs)were exposed to 5μg/mL lipopolysaccharide(LPS)for 24 h to establish a cell injury model.When treated with hESC-MSCs or mitochondria derived from hESC-MSCs,HGFs showed reduced expression of inflammatory genes,increased adenosine triphosphate(ATP)level,decreased reactive oxygen species(ROS)production,and enhanced mitochondrial function compared to the control.The average efficiency of isolated mitochondrial transfer by hESC-MSCs was determined to be 8.93%.Besides,a therapy of local mitochondrial injection in mice with LPS-induced periodontitis showed a reduction in inflammatory gene expression,as well as an increase in both the mitochondrial number and the aspect ratio in gingival tissues.In conclusion,our results indicate that mitochondria derived from hESC-MSCs can reduce the inflammatory response and improve mitochondrial function in HGFs,suggesting that the transfer of mitochondria between hESC-MSCs and HGFs serves as a potential mechanism underlying the therapeutic effect of stem cells.
基金supported by the National Natural Science Foundation of China(82072025,82072026,82102162,and 82303886)the“Leading Goose”Research and Development Program of Zhejiang Province(2023C03062)+1 种基金the National Natural Science Foundation of Zhejiang Province(LY22H160040 and LQ22H180010)the Key Research and Development Project of Lishui City(2022ZDYF12,2022ZDYF20,and 2022ZDYF20).
文摘Background:Radiofrequency ablation(RFA)is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality.Understanding the biological process related with RFA treatment is important for improving treatment strategy.This study aimed to identify the critical targets for regulating the efficacy of RFA.Methods:The RFA treatment in hepatocellular carcinoma(HCC)tumor models in vivo,was analyzed by RNA sequencing technology.The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells.Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase(MELK).Results:It was found that RFA treatment upregulated MELK expression,and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response,including anti-tumoral macrophage polarization and increased CD8+T cell cytotoxicity in HCC.Mechanically,MELK binds to fatty acid-binding protein 5(FABP5),and affects its ubiquitination through the K48R pathway to increase its stability,thereby activating protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling axis to weaken the RFA-mediated antitumor effect.In addition,the synthesis of arginylglycylaspartic acid(RGD)-lipid nanoparticles(LNPs)targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC.Conclusions:MELK is a therapeutic target by regulating RFA efficacy in HCC,and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer.
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.
