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Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation

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Cell Research 2007年第1期17卷 37-41页

作者： Gen-Sheng Feng~1 ~1programs in signal transduction and stem cells and regeneration,Burnham Institute for Medical Research,10901 N.Torrey Pines Rd,La Jolla,CA 92037,USA programs in signal transduction and stem cells and regeneration Burnham Institute for Medical Research La Jolla USA

A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem(ES) cell *** cell properties are dictated by specific transcription factors and epigenetic processes suchas DNA methylation and chromatin *** cytokines/growth factors have been identified as critical ES ***,there is a gap in our knowledge of the intracellular signaling pathways linking extracellular signalsto transcriptional regulation in ES *** short review discusses the physiological role of Shp2,a cytoplasmic tyro-sine phosphatase,in the molecular switch governing ES cell self-renewal versus ***2 promotes ES celldifferentiation,mainly through bi-directional modulation of Erk and Stat3 *** of Shp2 in mouse E S cellsresults in more efficient *** observation provides the impetus to develop Shp2 inhibitors for maintenanceand amplification of ES cells in culture.

关键词： Shp2 embryonic stem cell pluripotency embryonic stem cell self-renewal embryonic stem cell differentiation

Mandible exosomal ssc-mir-133b regulates tooth development in miniature swine via endogenous apoptosis

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Bone Research 2018年第4期6卷 408-417页

作者： Ye Li Xinxin Wang Jiali Ren Xiaoshan Wu Guoqing Li Zhipeng Fan Chunmei Zhang Ang Li Songlin Wang Molecular Laboratory for Gene Therapy and Tooth regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of Stomatology Xi'an Jiaotong University Laboratory of Molecular signaling and stem Cell Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Department of Biochemistry and Molecular Biology Capital Medical University School of Basic Medical Sciences

signal transduction between different organs is crucial in the normal development of the human body. As an important medium for signal communication, exosomes can transfer important information, such as microRNAs(miRNAs), from donors to *** are known to fine-tune a variety of biological processes, including maxillofacial development; however, the underlying mechanism remains largely unknown. In the present study, transient apoptosis was found to be due to the expression of a miniature swine maxillofacial-specific miRNA, ssc-mir-133b. Upregulation of ssc-mir-133b resulted in robust apoptosis in primary dental mesenchymal cells in the maxillofacial region. Cell leukemia myeloid 1(Mcl-1) was verified as the functional target, which triggered further downstream activation of endogenous mitochondria-related apoptotic processes during tooth *** importantly, mandible exosomes were responsible for the initial apoptosis signal. An animal study demonstrated that ectopic expression of ssc-mir-133 b resulted in failed tooth formation after 12 weeks of subcutaneous transplantation in nude mice. The tooth germ developed abnormally without the indispensable exosomal signals from the mandible.

关键词： In As

Human organoids in basic research and clinical applications

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signal transduction and Targeted Therapy 2022年第6期7卷 2010-2026页

作者： Xiao-Yan Tang Shanshan Wu Da Wang Chu Chu Yuan Hong Mengdan Tao Hao Hu Min Xu Xing Guo Yan Liu Institute for stem Cell and Neural regeneration School of PharmacyState Key Laboratory of Reproductive MedicineKey Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjingChina Department of Neurobiology School of Basic Medical SciencesNanjing Medical UniversityNanjingChina

Organoids are three-dimensional(3D)miniature structures cultured in vitro produced from either human pluripotent stem cells(hPSCs)or adult stem cells(AdSCs)derived from healthy individuals or patients that recapitulate the cellular heterogeneity,structure,and functions of human *** advent of human 3D organoid systems is now possible to allow remarkably detailed observation of stem cell morphogens,maintenance and differentiation resemble primary tissues,enhancing the potential to study both human physiology and developmental *** they are similar to their original organs and carry human genetic information,organoids derived from patient hold great promise for biomedical research and preclinical drug testing and is currently used for personalized,regenerative medicine,gene repair and transplantation *** recent decades,researchers have succeeded in generating various types of organoids mimicking in vivo ***,we provide an update on current in vitro differentiation technologies of brain,retinal,kidney,liver,lung,gastrointestinal,cardiac,vascularized and multi-lineage organoids,discuss the differences between PSC-and AdSC-derived organoids,summarize the potential applications of stem cell-derived organoids systems in the laboratory and clinic,and outline the current challenges for the application of organoids,which would deepen the understanding of mechanisms of human development and enhance further utility of organoids in basic research and clinical studies.

关键词： organs clinical generating

Functional hair follicle regeneration:an updated review

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signal transduction and Targeted Therapy 2021年第3期6卷 723-733页

作者： Shuaifei Ji Ziying Zhu Xiaoyan Sun Xiaobing Fu Research Center for Tissue Repair and regeneration affiliated to the Medical Innovation Research Department and 4th Medical Center PLA General Hospital and PLA Medical CollegePLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin InjuryRepair and RegenerationResearch Unit of Trauma CareTissue Repair and RegenerationChinese Academy of Medical Sciences2019RU051Beijing 100048People's Republic of China

The hair follicle(HF)is a highly conserved sensory organ associated with the immune response against pathogens,thermoregulation,sebum production,angiogenesis,neurogenesis and wound *** recent advances in lineage-tracing techniques and the ability to profile gene expression in small populations of cells have increased the understanding of how stem cells operate during hair growth and regeneration,the construction of functional follicles with cycling activity is still a great challenge for the hair research field and for translational and clinical *** that hair formation and cycling rely on tightly coordinated epithelial-mesenchymal interactions,we thus review potential cell sources with HF-inducive capacities and summarize current bioengineering strategies for HF regeneration with functional restoration.

关键词： healing wound hair

Immunity-and-matrix-regulatory cells enhance cartilage regeneration for meniscus injuries: a phase I dose-escalation trial

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signal transduction and Targeted Therapy 2023年第12期8卷 5873-5886页

作者： Liangjiang Huang Song Zhang Jun Wu Baojie Guo Tingting Gao Sayed Zulfiqar Ali Shah Bo Huang Yajie Li Bo Zhu Jiaqi Fan Liu Wang Yani Xiao Wenjing Liu Yao Tian Zhengyu Fang Yingying Lv Lingfeng Xie Sheng Yao Gaotan Ke Xiaolin Huang Ying Huang Yujuan Li Yi Jia Zhongwen Li Guihai Feng Yan Huo Wei Li Qi Zhou Jie Hao Baoyang Hu Hong Chen Department of Rehabilitation Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina National stem Cell Resource Center State Key Laboratory of Stem Cell and Reproductive BiologyInstitute of ZoologyInstitute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina Beijing Institute for stem Cell and Regenerative Medicine BeijingChina Department of Radiology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina stem Cell Research Center Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Department of Orthopedics Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina University of Chinese Academy of Sciences BeijingChina Beijing Key Lab for Pre-clinical Safety Evaluation of Drugs National Center for Safety Evaluation of DrugsNational Institutes for Food and Drug ControlBeijingChina Beijing Zephyrm Biotechnologies Co. Ltd.BeijingChina

Immunity-and-matrix-regulatory cells(IMRCs)derived from human embryonic stem cells have unique abilities in modulating immunity and regulating the extracellular matrix,which could be mass-produced with stable biological *** resemblance to mesenchymal stem cells(MSCs)in terms of self-renew and tri-lineage differentiation,the ability of IMRCs to repair the meniscus and the underlying mechanism remains ***,we showed that IMRCs demonstrated stronger immunomodulatory and pro-regenerative potential than umbilical cord MSCs when stimulated by synovial fluid from patients with meniscus *** injection into the knees of rabbits with meniscal injury,IMRCs enhanced endogenous fibrocartilage *** the dose-escalating phase I clinical trial(NCT03839238)with eighteen patients recruited,we found that intra-articular IMRCs injection in patients was safe over 12 months ***,the effective results of magnetic resonance imaging(MRI)of meniscus repair and knee functional scores suggested that 5×107 cells are optimal for meniscus injury *** summary,we present the first report of a phase I clinical trial using IMRCs to treat meniscus *** results demonstrated that intra-articular injection of IMRCs is a safe and effective therapy by providing a permissive niche for cartilage regeneration.

关键词： meniscus injuries cartilage

MiR146a-loaded engineered exosomes released from silk fibroin patch promote diabetic wound healing by targeting IRAK1

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signal transduction and Targeted Therapy 2023年第3期8卷 1224-1236页

作者： Qiankun Li Wenzhi Hu Qilin Huang Jie Yang Bingmin Li Kui Ma Qian Wei Yaxi Wang Jianlong Su Mengli Sun Shengnan Cui Rungong Yang Haihong Li Xiaobing Fu Cuiping Zhang Department of Tissue Repair and regeneration The First Medical CenterChinese PLA General HospitalBeijing 100853China Research Center for Tissue Repair and regeneration Medical Innovation Research Department and the Fourth Medical CenterChinese PLA General HospitalBeijing 100048China Dermatology Department The Fourth Medical CenterChinese PLA General HospitalBeijing 100048China Research Unit of Trauma Care Tissue Repair and RegenerationChinese Academy of Medical Sciences2019RU051Beijing 100048China PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury Repair and RegenerationBeijing 100048China School of Medicine NanKai UniversityTianjing 300071China Department of Wound Repair and Dermatologic Surgery Taihe HospitalHubei University of MedicineShiyan 442000China

Unhealable diabetic wounds need to be addressed with the help of newer,more efficacious *** combined with biomaterials for sustained delivery of therapeutic agents are expected to bring new hope for chronic wound ***,the engineered exosomes modified for efficiently loading miR146a and attaching to silk fibroin patch(SFP)were demonstrated to promote diabetic wound *** fibroin binding peptide(SFBP)was screened through phage display,and SFBP-Gluc-MS2(SGM)and pac-miR146a-pac fusion protein were *** designed exosomes(SGM-Exos,miR146a-Exos,and SGM-miR146a-Exos)were isolated from the engineered placental mesenchymal stem cells(PMSCs)transduced with SGM or/and pac-miR146a-pac *** signals indicated SGM-Exo@SFP markedly increased the binding rate and the stability of ***,the loading efficiency of miR146a in SGM-miR146a-Exos was ten-fold higher than that in *** to untreated,SGM-miR146a-Exo-only treated,and SFP-only treated groups,SGM-miR146a-Exo@SFP drived wound healing associated with less inflammation,collagen deposition,and *** transcriptomics analysis suggested anti-inflammatory and regenerative effects with SGM-miR146a-Exo@SFP ***,we show efficient exosome@biomaterial-based miRNA delivery systems for regenerative medicine and tissue engineering.

关键词： miR146a wound healing

Cellular rejuvenation:molecular mechanisms and potential therapeutic interventions for diseases

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signal transduction and Targeted Therapy 2023年第4期8卷 1571-1609页

作者： Shuaifei Ji Mingchen Xiong Huating Chen Yiqiong Liu Laixian Zhou Yiyue Hong Mengyang Wang Chunming Wang Xiaobing Fu Xiaoyan Sun Research Center for Tissue Repair and regeneration Affiliated to Medical Innovation Research Department and 4th Medical Center PLA General Hospital and PLA Medical CollegePLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin InjuryRepair and RegenerationResearch Unit of Trauma CareTissue Repair and RegenerationChinese Academy of Medical Sciences2019RU051Beijing 100048P.R.China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipa999078 Macao SARChina

The ageing process is a systemic decline from cellular dysfunction to organ degeneration,with more predisposition to deteriorated *** refers to giving aged cells or organisms more youthful characteristics through various techniques,such as cellular reprogramming and epigenetic *** great leaps in cellular rejuvenation prove that ageing is not a one-way street,and many rejuvenative interventions have emerged to delay and even reverse the ageing *** the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative ***,we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation,and the targeted cells and core mechanisms involved in this ***,we critically summarize the latest advances in state-of-art strategies of cellular *** rejuvenation methods also provide insights for treating specific ageing-related diseases,including cellular reprogramming,the removal of senescence cells(SCs)and suppression of senescence-associated secretory phenotype(SASP),metabolic manipulation,stem cells-associated therapy,dietary restriction,immune rejuvenation and heterochronic transplantation,*** potential applications of rejuvenation therapy also extend to cancer ***,we analyze in detail the therapeutic opportunities and challenges of rejuvenation *** rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.

关键词： therapeutic mechanisms potential

EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

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signal transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： Keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell Jun Okabe Ishant Khurana Thomas Karagiannis Julia J.Liang Lina Mariana Thomas Loudovaris Thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release *** type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-*** of these cells leads to a lifelong dependence on exogenous insulin administration for ***,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell *** and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation *** transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 *** the present study,we show that transient stimulation of exocrine cells,derived from juvenile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell *** transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin *** EZH2 is fundamental toβ-cell regenerative *** pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex *** pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer's tau pathology

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signal transduction and Targeted Therapy 2022年第7期7卷 2545-2554页

作者： Shichao Huang Zhen Zhang Junwei Cao Yongchun Yu Gang Pei State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of Sciences200031 ShanghaiChina Institutes of Brain Science State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain ScienceFudan University200032 ShanghaiChina Shanghai Key Laboratory of signaling and Disease Research Laboratory of Receptor-based BiomedicineThe Collaborative Innovation Center for Brain ScienceSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina Institute for stem Cell and regeneration Chinese Academy of SciencesBeijingChina

The apolipoprotein E4(APOE4)genotype is one of the strongest genetic risk factors for Alzheimer’s disease(AD),and is generally believed to cause widespread pathological alterations in various types of brain ***,we developed a novel engineering method of creating the chimeric human cerebral organoids(chCOs)to assess the differential roles of APOE4 in neurons and ***,the astrogenic factors NFIB and SOX9 were introduced into induced pluripotent stem cells(iPSCs)to accelerate the induction of *** the above induced iPSCs were mixed and cocultured with noninfected iPSCs under the standard culturing condition of cerebral *** anticipated,the functional astrocytes were detected as early as 45 days,and it helped more neurons matured in chCOs in comparation of the control human cerebral organoids(hCOs).More interestingly,this method enabled us to generate chCOs containing neurons and astrocytes with different genotypes,namely APOE3 or ***,it was found in chCOs that astrocytic APOE4 already significantly promoted lipid droplet formation and cholesterol accumulation in neurons while both astrocytic and neuronal APOE4 contributed to the maximum *** notably,we observed that the cooccurrence of astrocytic and neuronal APOE4 were required to elevate neuronal phosphorylated tau levels in chCOs while Aβlevels were increased in chCOs with neuronal ***,our results not only revealed the essence of both neuronal and astrocytic APOE4 for tau pathology,but also suggested chCOs as a valuable pathological model for AD research and drug discovery.

关键词： cerebral alterations neuronal