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Loss of Tet hydroxymethylase activity causes mouse embryonic stem cell differentiation bias and developmental defects

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Science China Life Sciences 2024年第10期67卷 2132-2148页

作者： Mengting Wang Liping Wang Yanxin Huang Zhibin Qiao Shanru Yi Weina Zhang Jing Wang Guang Yang Xinyu Cui Xiaochen Kou Yanhong Zhao Hong Wang Cizhong Jiang Shaorong Gao Jiayu Chen clinical and translational research Center of Shanghai First Maternity and Infant Hospital Shanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji University Frontier Science Center for stem cell research Tongji University Shanghai Tenth People's Hospital School of MedicineTongji University Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education Orthopaedic Department of Tongji HospitalTongji University Shanghai institute of stem cell research and clinical translation

The TET family is well known for active DNA demethylation and plays important roles in regulating transcription, the epigenome and development. Nevertheless, previous studies using knockdown（KD） or knockout（KO） models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles, as well as compensatory effects among TET family members, which has made the understanding of the enzymatic role of TET not accurate enough. To solve this problem, we successfully generated mice catalytically inactive for specific Tet members(Tetm/m). We observed that, compared with the reported KO mice, mutant mice exhibited distinct developmental defects, including growth retardation, sex imbalance, infertility, and perinatal lethality. Notably, Tetm/mmouse embryonic stem cells（mESCs） were successfully established but entered an impaired developmental program, demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation. Intriguingly, Tet3, traditionally considered less critical for m ESCs due to its lower expression level, had a significant impact on the global hydroxymethylation, gene expression, and differentiation potential of mESCs. Notably, there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation. In summary, our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.

关键词： Tet hydroxymethylase activity mESCs DNA demethylation 5hmC

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Programmable synthetic receptors:the next-generation of cell and gene therapies

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Signal Transduction and Targeted Therapy 2024年第2期9卷 376-400页

作者： Fei Teng Tongtong Cui Li Zhou Qingqin Gao Qi Zhou Wei Li University of Chinese Academy of Sciences Beijing 101408China State Key Laboratory of stem cell and Regenerative Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China institute for stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing institute for stem cell and Regenerative Medicine Beijing 100101China

cell and gene therapies hold tremendous promise for treating a range of difficult-to-treat ***,concerns over the safety and efficacy require to be further addressed in order to realize their full *** receptors,a synthetic biology tool that can precisely control the function of therapeutic cells and genetic modules,have been rapidly developed and applied as a powerful *** designed and engineered,they can be applied to finetune the therapeutic activities,i.e.,to regulate production of dosed,bioactive payloads by sensing and processing user-defined signals or *** review provides an overview of diverse synthetic receptor systems being used to reprogram therapeutic cells and their wide applications in biomedical *** a special focus on four synthetic receptor systems at the forefront,including chimeric antigen receptors(CARs)and synthetic Notch(synNotch)receptors,we address the generalized strategies to design,construct and improve synthetic ***,we also highlight the expanding landscape of therapeutic applications of the synthetic receptor systems as well as current challenges in their clinical translation.

关键词： synthetic landscape payload

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Extracellular vesicles derived from mesenchymal stem cells:the wine in Hebe's hands to treat skin aging

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Precision clinical Medicine 2024年第2期7卷 170-189页

作者： Qixiang Gui Neng Ding Zuochao Yao Minjuan Wu Ruifeng Fu Yue Wang Yunpeng Zhao Lie Zhu Department of Plastic and Reconstructive Surgery Second Affliated Hospital of Naval Medical University(Shanghai Changzheng Hospital)Shanghai 20o001China Department of Plastic and Reconstructive Surgery of Shanghai East Hospital School of MedicineTongji UniversityShanghai 200120China Department of Histology and Embryology Naval Medical UniversityShanghai 200433China Shanghai Key Laboratory of cell Engineering Translational Medical Research CenterNaval Medical UniversityShanghai 200433China hanghai institute of stem cell research and clinical translation Shanghai 200092China

Owing to its constant exposure to the external environment and various stimuli,skin ranks among the organs most vulnerable to manifestations of *** and delaying skin aging has become one of the prominent research subjects in recent *** stem celis(MsCs)are multipotent stem cells derived from mesoderm with high self-renewal ability and multilineage differentiation ***-derived extracellular vesicles(MSC-EVs)are nanoscale biological vesicles that facilitate intercellular communication and regulate biological *** studies have shown that MSC-EVs have potential applications in anti-aging therapy due to their anti-inflammatory,anti-oxidative stress,and wound healing promoting *** review presents the latest progress of MSC-EVs in delaying skin *** mainly includes the MSC-EVs promoting the proliferation and migration of keratinocytes and fibroblasts,reducing the expression of matrix metalloproteinases,resisting oxidative stress,and regulating *** then briefly discuss the recently discovered treatment methods of MSc-EVs in the field of skin ***,the advantages and limitations of EV-based treatments are also presented.

关键词： mesenchymal stem cell extracellular vesicles exosomes skin aging anti-aging photoaging

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Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 568-580页

作者： Hao ZHANG Xinshu WANG Bo HU Peicheng LI Yierfan ABUDUAINI Hongmei ZHAO Ayinaer JIEENSIHAN Xishuang CHEN Shiyu WANG Nuojin GUO Jian YUAN Yunhui LI Lei LI Yuntong YANG Zhongmin LIU Zhaosheng TANG Hua WANG Department of Endocrinology Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China research Center for translational Medicine Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China Department of Cardiology Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China Department of Biochemistry and Molecular Biology School of MedicineTongji UniversityShanghai 200331China Shanghai institute of stem cell research and clinical translation Shanghai East HospitalShanghai 200120China Ji’an Hospital Shanghai East HospitalJi’an 343000China

diabetes mellitus(DM)is a disease syndrome characterized by chronic hyperglycaemia.A long-term high-glucose environment leads to reactive oxygen species(ROS)production and nuclear DNA *** umbilical cord mesenchymal stem cell(HUcMSC)infusion induces significant antidiabetic effects in type 2 diabetes mellitus(T2DM)***-like growth factor 1(IGF1)receptor(IGF1R)is important in promoting glucose metabolism in diabetes;however,the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains *** this study,a DM rat model was induced with high-fat diet feeding and streptozotocin(STZ)administration and rats were infused four times with *** glucose,interleukin-6(IL-6),IL-10,glomerular basement membrane,and renal function were *** that interacted with IGF1R were determined through coimmunoprecipitation *** expression of IGF1R,phosphorylated checkpoint kinase 2(p-CHK2),and phosphorylated protein 53(p-p53)was examined using immunohistochemistry(IHC)and western blot ***-linked immunosorbent assay(ELISA)was used to determine the serum levels of 8-hydroxydeoxyguanosine(8-OHdG).Flow cytometry experiments were used to detect the surface markers of *** identification of the morphology and phenotype of HUcMSC was performed by way of oil red“O”staining and Alizarin red *** rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane,increased the expression of IGF1 and ***1R interacted with CHK2,and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown *** cisplatin was used to induce DNA damage,the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin *** infusion ameliorated abnormalities and preserved kidney structure and function in DM *** expression of IGF1,IGF1R,p-CHK2,and p-p53,and the level of 8-OHdG in the DM group increased sign

关键词： Insulin-like growth factor 1 receptor(IGF1R) Checkpoint kinase 2(CHK2) Protein 53(p53) Diabetes mellitus Human umbilical cord mesenchymal stem cell(HUcMSC) DNA damage repair

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Pivotal role for long noncoding RNAs in zygotic genome activation in mice

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Science China(Life Sciences) 2024年第5期67卷 958-969页

作者： Kang Chen Wenju Liu Jiang Zhu Xiaochen Kou Yanhong Zhao Hong Wang Cizhong Jiang Shaorong Gao Lan Kang institute for Regenerative Medicine Shanghai East HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200120China Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education Orthopaedic Department of Tongji HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Frontier Science Center for stem cell research Tongji UniversityShanghai 200092China clinical and translation research Center of Shanghai First Maternity&Infant Hospital School of Life Sciences and TechnologyTongji UniversityShanghai 200092China institute of Biophysics Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

Vertebrate life begins with fertilization,and then the zygote genome is activated after transient silencing,a process termed zygotic genome activation(ZGA).Despite its fundamental role in totipotency and the initiation of life,the precise mechanism underlying ZGA initiation remains *** existence of minor ZGA implies the possible critical role of noncoding RNAs in the initiation of ***,we delineate the expression profile of long noncoding RNAs(lncRNAs)in early mouse embryonic development and elucidate their critical role in minor *** with protein-coding genes(PCGs),lncRNAs exhibit a stronger correlation with minor *** H3K9me3 profiles can be observed between lncRNA genes and PCGs,and the enrichment of H3K9me3 before ZGA might explain the suspended expression of major ZGA-related PCGs despite possessing PolII ***,we identified the presence of PolII-enriched MuERV-L around the transcriptional start site of minor ZGA-related lncRNAs,and these repeats are responsible for the activation of minor ZGA-related lncRNAs and subsequent embryo *** study suggests that MuERV-L mediates minor ZGA lncRNA activation as a critical driver between epigenetic reprogramming triggered by fertilization and the embryo developmental program,thus providing clues for understanding the regulatory mechanism of totipotency and establishing bona fide totipotent stem cells.

关键词： ZGA lncRNA MuERV-L

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Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

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Neural Regeneration research 2024年第2期19卷 440-446页

作者： Sumei Liu Baoguo Liu Qian Li Tianqi Zheng Bochao Liu Mo Li Zhiguo Chen cell Therapy Center Beijing Institute of GeriatricsXuanwu HospitalCapital Medical UniversityNational Clinical Research Center for Geriatric Diseasesand Key Laboratory of Neurodegenerative DiseasesMinistry of EducationBeijingChina Center of Neural Injury and Repair Beijing Institute for Brain DisordersBeijingChina Center of Parkinson’s Disease Beijing Institute for Brain DisordersBeijingChina

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate *** a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury ***,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord *** neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury ***,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion *** of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the ***,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion ***-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

关键词： biomaterial fibrinogen functional recovery induced neural stem cell transplantation microenvironment microglia spinal cord injury thrombin

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Mesenchymal stem cell-derived exosomes: Versatile nanomaterials for skin wound treatment

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Nano research 2024年第4期17卷 2836-2856页

作者： Yuzhen Xiao Hexi Li Junhui Zhang Songyun Yang Chunsen Zhang Yizhou Huang Xin Tang Huiqi Xie Department of Orthopedic Surgery and Orthopedic research institute Laboratory of Stem Cell and Tissue EngineeringState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China School of Basic Medical Sciences and Forensic Medicine Sichuan UniversityChengdu 610041China West China School of Public Health and West China Fourth Hospital Sichuan UniversityChengdu 610041China Sports Medicine Center West China HospitalSichuan UniversityChengdu 610041China

Accumulating studies reveal that mesenchymal stem cells(MSCs)promote skin wound healing mainly through the paracrine ***,one of the crucial paracrine mediators in wound healing,are cell-derived nanosized membranous vesicles containing diverse bioactive *** the potent ability of modulating skin cell behaviors,MSC-derived exosomes(MSC-Exos)are regarded as a promising nanomaterial for regenerative wound *** hostile conditions,MSC-Exos are efficient in protecting skin cells from severe damage and restoring their *** to recent studies,MSC-Exos possess remarkable pro-healing effects in a variety of skin wounds,typically resulting in increased wound closure,inhibited scar tissue formation,and better restoration of skin *** further enhance the therapeutic potential of MSC-Exos,the development of applicable pretreatment strategies and the optimization of exosome delivery are under intensive ***,we summarize current research progress of MSC-Exos for skin wound treatment,with an emphasis on the biological effects of these nanovesicles,the repair mechanisms,and future challenges in clinical translation.

关键词： exosomes mesenchymal stem cells diabetic wounds burn wounds scar wound healing

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Single-cell transcriptomics of cardiac progenitors reveals functional subpopulations and their cooperative crosstalk in cardiac repair

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Protein & cell 2021年第2期12卷 152-157页

作者： Lei Gao Hongjie Zhang Jingyi Cui Lijuan Pei Shiqi Huang Yaning Mao Zhongmin Liu Ke Wei Hongming Zhu translational Medical Center for stem cell Therapy Institute for Regenerative MedicineShanghai East HospitalTongji University School of MedicineShanghai 200120China institute for Regenerative Medicine Shanghai East HospitalShanghai Institute of Stem Cell Research and Clinical TranslationShanghai Key Laboratory of Signaling and Disease ResearchFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

Dear Editor,Myocardial infarction is one of the leading causes of morbidity and ***/progenitor cells therapy has emerged as a promising strategy for the cardiac repair,especially those derived from cardiac tissue,have attracted worldwide attention(Tompkins et al.,2018).However,challenges and controversies remain in characterizing functional progenitors and explaining their mechanisms of action.

关键词： progenitor cardiac al.

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miRNA in cardiac development and regeneration

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cell Regeneration 2021年第1期10卷 156-176页

作者： Zhaohui Ouyang Ke Wei institute for Regenerative Medicine Shanghai East HospitalShanghai Institute of Stem Cell Research and Clinical TranslationShanghai Key Laboratory of Signaling and Disease ResearchFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092P.R.China

Ischemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalianhearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation,making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), aclass of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of posttranscriptionalgene expression, have been shown to play a crucial role in cardiac development and cardiomyocyteproliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth,while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given theirsmall size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targetsor tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition ofspecific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of proproliferationmiRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting thepower of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have beenshown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstratedpromising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such asuncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiacdevelopment and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, anddiscuss its potential as a new strategy for cardiac regeneration therapy.

关键词： microRNA heart cardiomyocyte development proliferation regeneration

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Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression

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Bone research 2023年第1期11卷 136-147页

作者： Aoyuan Fan Genbin Wu Jianfang Wang Laiya Lu Jingyi Wang Hanjing Wei Yuxi Sun Yanhua Xu Chunyang Mo Xiaoying Zhang Zhiying Pang Zhangyi Pan Yiming Wang Liangyu Lu Guojian Fu Mengqiu Ma Qiaoling Zhu Dandan Cao Jiachen Qin Feng Yin Rui Yue Department of Joint Surgery Shanghai East HospitalTongji University School of MedicineShanghai200092China Department of Orthopedic Surgery Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200240China institute for Regenerative Medicine Shanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai200092China Department of Cardiology Shanghai Tenth People’s HospitalTongji University School of MedicineShanghai200072China Shanghai institute of stem cell research and clinical translation Shanghai200120China Shanghai clinical research Center for Aging and Medicine Shanghai200040China

Fibroblast activation protein(Fap)is a serine protease that degrades denatured type I collagen,α2-antiplasmin and *** is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin(Oln).Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis(RA).However,whether Fap plays a critical role in osteoarthritis(OA)remains poorly ***,we found that Fap is significantly elevated in osteoarthritic synovium,while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in ***,we found that Fap degrades denatured type II collagen(Col II)and Mmp13-cleaved native Col ***-articular injection of r Fap significantly accelerated Col II degradation and OA *** contrast,Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in *** deletion of Oln significantly exacerbated OA progression,which was partially rescued by Fap deletion or ***-articular injection of r Oln significantly ameliorated OA *** together,these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

关键词： cartilage superficial inhibited

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