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4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

Protein & Cell 2023年第3期14卷 202-216页

作者： Yifang He Qianzhao Ji zeming wu Yusheng Cai Jian Yin Yiyuan Zhang Sheng Zhang Xiaoqian Liu Weiqi zhang Guang-Hui Liu Si Wang Moshi Song Jing Qu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 10o101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China University of Chinese Academy of Sciences Beijing 100049China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China National Laboratory of Biomacromolecules CAs Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101 China State Key Laboratory of Brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center Intermational Center for Aging and CancerBejing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China The Fifth People's Hospital of Chongqing Chongqing 400062China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.

关键词： 4E-BP1 mitochondria aging

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APOE-mediated suppression of the lncRNA MEG3 protects human cardiovascular cells from chronic inflammation

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Protein & Cell 2023年第12期14卷 908-913页

作者： Hongkai Zhao Kuan Yang Yiyuan Zhang Hongyu Li Qianzhao ji zeming wu Shuai Ma Si Wang Moshi Song Guang-Hui Liu Qiang Liu Weiqi Zhang Jing Qu Division of Life Sciences and Medicine School of Life SciencesUniversity of Science and Technology of ChinaHefei 230001China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Universityof Chinese Academy of Sciences Beijing100049China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University.Beijing100053China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Aging Biomarker Consortium Beijing 100101China 12Division of Life Sciences and Medicine Institute on Aging and Brain DisordersThe First Affiliated Hospital of USTCHefei National Laboratory for Physical Sciences at the MicroscaleUniversity of Science and Technology of ChinaHefei 230026China Neurodegenerative Disease Research Center University of Science and Technology of ChinaHefei 230026China CAS Key Laboratory of Brain Function and Disease University of Science and Technology of ChinaHefei 230026China Center for Excellence in Animal Evolution and Genetics Chinese Academy of SciencesKunming 650201China

Dear Editor,Cardiovascular diseases(CVDs)are the leading cause of death world-wide.Thus,diagnosing and treating CVD remains at the forefront for clinicians while identifying targetable disease mechanisms in preclinical models are focus areas for researchers and drug developers(Cai et al.,2022a).The polymorphic protein apolipoprotein E(APOE),central to lipid transport and metabolism,is well-recognized for the role of its isoforms as important predictors for human cardiovascular disorders and neurodegenerative diseases(Tudorache et al.,2017).Plasma APOE is generated primarily from liver hepatocytes,accounting for around 75%of the APOE production from the whole body(Getz and Reardon,2009),and plays important functional roles in monocytes/macrophages,adipocytes,and the central nervous system(Kockx et al.,2018).However,despite the fact that APOE is widely expressed in different mammalian cells,studies on the functional roles of APOE mostly focus on its extracellular secreted form,and the specific effects of APOE,particularly intracellular form in cell types closely related to human cardiovascular diseases are therefore still poorly understood.

关键词： cardiovascular metabolism

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Hyperthermia differentially affects specific human stem cells and their differentiated derivatives

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Protein & Cell 2022年第8期13卷 615-622页

作者： Si Wang Fang Cheng Qianzhao Ji Moshi Song zeming wu Yiyuan Zhang Zhejun Ji Huyi Feng Juan Carlos Izpisua Belmonte Qi Zhou Jing Qu Wei Li Guang-Hui Liu Weiqi Zhang Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical University 100053 Beijing China Aging Translational Medicine Center International Center for Aging and Cancer Xuanwu Hospital Capital Medical University 100053 Beijing China Chongqing Renji Hospital University of Chinese Academy of Sciences 400062 Chongqing China National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences 100101 Beijing China University of Chinese Academy of Sciences 100049 Beijing China State Key Laboratory of Membrane Biology Institute of Zoology Chinese Academy of Sciences 100101 Beijing China Institute for Stem Cell and Regeneration Chinese Academy of Sciences 100101 Beijing China Beijing Institute for Stem Cell and Regenerative Medicine 100101 Beijing China State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences 100101 Beijing China Gene Expression Laboratory Salk Institute for Biological Studies La Jolla CA USA CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences 100101 Beijing China China National Center for Bioinformation 100101 Beijing China

Dear Editor,The human body operates optimally at a core temperature of 37 degrees Celsius.Homeostasis at this temperature is essential for cellular and physiological functions(Cheshire,2016).However,infectious diseases,inflammation,injury,neoplasia,and elevated climate temperature can cause a regulated rise in body core temperature,i.e.,fever(Pasi-khova et al,2017).Indeed,an acute or chronic increase in temperature leads to detrimental effects on vasculature by altering a number of indices of vascular structure and function(DuBose et al.,1998).

关键词： elevated inflammation acute

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Large-scale chemical screen identifies Gallic acid as a geroprotector for human stem cells

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Protein & Cell 2022年第7期13卷 532-539页

作者： Hezhen Shan Lingling Geng Xiaoyu Jiang Moshi Song Jianxun Wang Zunpeng Liu Xiao Zhuo zeming wu Jianli Hu Zhejun Ji Si Wang Piu Chan Jing Qu Weiqi Zhang Guang-Hui Liu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Aging Translational Medicine Center Xuanwu HospitalCapital Medical UniversityBeijing 100053China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China

Dear Editor,The interventions that slow aging or promote healthy aging may provide preventative measures for age-related diseases(Zhang et al.,2015).Therefore,it is crucial to identify drugs that target aging-related pathologies and improve health-span in geroscience research.Using model organisms such as C.elegans and rodents,several small molecules capable of alleviating the onset or progression of aging,including rapamycin,nicotinamide mononucleotide,and metformin,have been discovered(Partridge et al.,2020).However,the safety and efficacy of these chemicals still need in-depth evaluation before clinical applications(Partridge et al.,2020).As a result,it is necessary to identify additional compounds with geroprotective effects for human cells to counteract the general trend of populational aging.However,transforming a promising compound into an approved drug requires enormous resources.Alternatively,repurposing previously approved drugs for new clinical applications offers a more efficient and less costly path toward drug develop-ment.Therefore,testing U.S.Food and Drug Administration(FDA)-approved drugs for geroprotective effects may dis-covernew therapeutics that have already been stringently tested in humans for safety.

关键词： drugs protective al.

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mTORC2/RICTOR exerts differential levels of metabolic control in human embryonic,mesenchymal and neural stem cells

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Protein & Cell 2022年第9期13卷 676-682页

作者： Qun Chu Feifei Liu Yifang He Xiaoyu Jiang Yusheng Cai zeming wu Kaowen Yan Lingling Geng Yichen Zhang Huyi Feng Kaixin Zhou Si Wang Weiqi Zhang Guang-Hui Liu Shuai Ma Jing Qu Moshi Song State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane 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 Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China University of Chinese Academy of Sciences Beijing 100049China Aging Translational Medicine Center International Center for Aging and CancerXuanwu HospitalCapital Medical UniversityBeijing 100053China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Chongqing Renji Hospital University of Chinese Academy of SciencesChongqing 400062China College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China

Dear Editor,Stem cells,including pluripotent stem cells and adult stem cells,possess the remarkable capability of being able to selfrenew while at the same time having potential to differentiate into different cell lineages and functionally distinct cell types.Human embryonic stem cells(hESCs)can differentiate into all adult stem cell types,including human mesenchymal stem cells(hMSCs)and human neural stem cells(hNSCs),but can also give rise to all terminally differentiated cell types(Wang et al.,2021a).Through the continuous replenishment of differentiated cells,stem cells support tissue homeostasis and respond to tissue injuries.Given the promising applications of stem cells in cell therapy and regenerative medicine,insights into molecular events underlying stem cell maintenance,self-renewal ability and pluripotency,continue to garner strong interest(Shan et al.,2021).Although metabolic pathways have been implicated in the reciprocal regulations of stem cell self-renewal and differentiation as well as organ homeostatic maintenance(Garcia-Prat et al.,2017),central aspects of how metabolic requirements differ and are regulated across the various types of human stem cells in our body remain enigmatic.

关键词： injuries homeostasis neural

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Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis

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Protein & Cell 2022年第3期13卷 220-226页

作者： Jinghui Lei Xiaoyu Jiang Wei Li Jie Ren Datao Wang Zhejun Ji zeming wu Fang Cheng Yusheng Cai Zheng-Rong Yu Juan Carlos Izpisua Belmonte Chunyi Li Guang-Hui Liu Weiqi Zhang Jing Qu Si Wang Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center Xuanwu HospitalCapital Medical UniversityBeijing 100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Institute of Antler Science and Product Technology Changchun Sci-Tech UniversityChangchun 130000China University of Chinese Academy of Sciences Beijing 100049China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Department of Orthopaedics Peking University First HospitalBeijing 100034China Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCAUSA

Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered stem cells,partially due to immunological rejection,constitute major hurdles for the clinical implementation of stem cell therapy(Lei et al.,2021a).Since mounting evidence showed that several types of stem cells mainly exert their therapeutic effects through the secretion of paracrine effects,exosomes,which are released by stem cells and execute most paracrine functions,have begun to draw attention in the field(Tran and Damaser,2015).Exosomes are membrane-enclosed vesicles with an average diameter of∼100 nanometers secreted by the cells,containing cytokines.

关键词： Exosomes holds mount

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FTO stabilizes MIS12 and counteracts senescence

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Protein & Cell 2022年第12期13卷 954-960页

作者： Sheng Zhang zeming wu Yue Shi Si Wang Jie Ren Zihui Yu Daoyuan Huang Kaowen Yan Yifang He Xiaoqian Liu Qianzhao Ji Beibei Liu Zunpeng Liu Jing Qu Guang-Hui Liu Weimin Ci Xiaoqun Wang Weiqi Zhang State Key Laboratory of Brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute of BiophysicsChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric DisordersXuanwu HospitalCapital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Center for Aging and CancerXuanwu HospitalCapital Medical UniversityBeijing 100053China Chongqing Renji Hospital University of Chinese Academy of SciencesChongqing 400062China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Brain Disorders Beijing 100069China

Dear Editor, N6-methyladenosine(m6A)is an abundant epitranscriptomic modification that regulates messenger RNA(mRNA)biology.The m6A modification regulates mRNA splicing,transport,stability,and translation through coordinated activities by methyltransferases(writers),binding proteins(readers),and demethylases(erasers)(Huang et al.,2020;wu et al.,2020).Among m6A regulators,fat mass of obesity-associ-ated protein(FTO),is the first discovered eraser with RNA m6A demethylation activity(Jia et al.,2011).Since then,FTO has been reported to play m6A-dependent roles in a variety of physiological processes including adipogenesis,neuro-genesis and tumorigenesis(Fischer et al.,2009;Li et al.,2017;Huang et al.,2020).Consequently,FTO deficiency in mice leads to dramatic phenotypes,such as decreased fat mass and impaired brain development(Fischer et al.,2009;Li et al.,2017).Similarly,inhibition of FTO reduces tumori-genesis in multiple types of cancer models,while FTO is highly expressed in many cancers(Huang et al.,2020).

关键词： Fischer impaired

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Glutathione restoration: a sword to combat skeletal muscle stem cell aging

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Life Metabolism 2023年第3期2卷 5-7页

作者： zeming wu Jie Ren Guang-Hui Liu State Key Laboratory of Membrane 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 CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Center for Aging and CancerXuanwu HospitalCapital Medical UniversityBeijing 100053China

In a recent study published in Cell Metabolism,Thomas A.Rando and colleagues reported a critical role of dysregulated glutathione(GSH)metabolism in driving the aging process of skeletal muscle stem cells(MuSCs),uncovering a novel mechanism underlying the divergent responses of quiescent stem cells to environmental stressors with age,thus providing a potentially accessible target to alleviate age-associated skeletal muscle degeneration.

关键词： skeletal metabolism degeneration

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SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer

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Protein & Cell 2020年第7期11卷 483-504页

作者： Shijia Bi Zunpeng Liu zeming wu Zehua Wang Xiaoqian Liu Si Wang Jie Ren Yan Yao Weiqi Zhang Moshi Song Guang-Hui Liu Jing Qu State Key Laboratory of Stem Cell and Reproductive Biology Instiute of ZoologyChinese Academy of SciencesBejing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBejing 100101China Beiing Institute for Brain Disorders Advanced Innovation Center for Human Brain ProtectionNational Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China CAS Key Laboratory of Genomic and Precision Medicine Beiing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Bejing 100101China Institute for Stem cell and Regeneration Chinese Academy of SciencesBeiing 100101China University of Chinese Academy of Sciences Beijing 100049China Department of Cardiology Bejing Anzhen HospitalCapital Medical UniversityBeijing 100029China

SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.

关键词： SIRT7 stem cell aging LINE1 cGAS STING

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Super-resolution fluorescence-assisted diffraction computational tomography reveals the threedimensional landscape of the cellular organelle interactome

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Light(Science & Applications) 2020年第1期9卷 1889-1903页

作者： Dashan Dong Xiaoshuai Huang Liuju Li Heng Mao Yanquan Mo Guangyi Zhang Zhe Zhang Jiayu Shen Wei Liu zeming wu Guanghui Liu Yanmei Liu Hong Yang Qihuang Gong Kebin Shi Liangyi Chen State Key Laboratory for Mesoscopic Physics and Frontiers Science Center for Nano-optoelectronics School of PhysicsPeking UniversityBeijing 100871China Collaborative Innovation Center of Extreme Optics Shanxi UniversityTaiyuanShanxi 030006China State Key Laboratory of Membrane Biology Beijing Key Laboratory of Cardiometabolic Molecular MedicineInstitute of Molecular MedicinePeking UniversityBeijing 100871China School of Mathematical Sciences Peking UniversityBeijing 100871China School of Software and Microelectronics Peking UniversityBeijing 100871China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China National Laboratory of Biomacromolecules Chinese Academy of Sciences Center for Excellence in BiomacromoleculesInstitute of BiophysicsBeijing 100101China Institute for Brain Research and Rehabilitation(IBRR) Guangdong Key Laboratory of Mental Health and Cognitive ScienceSouth China Normal UniversityGuangzhouChina Collaborative Innovation Center of Quantum Matter Peking UniversityBeijing 100871China PKU-IDG/McGovern Institute for Brain Research Beijing 100871China

The emergence of super-resolution(SR)fluorescence microscopy has rejuvenated the search for new cellular substructures.However,SR fluorescence microscopy achieves high contrast at the expense of a holistic view of the interacting partners and surrounding environment.Thus,we developed SR fluorescence-assisted diffraction computational tomography(SR-FACT),which combines label-free three-dimensional optical diffraction tomography(ODT)with two-dimensional fluorescence Hessian structured illumination microscopy.The ODT module is capable of resolving the mitochondria,lipid droplets,the nuclear membrane,chromosomes,the tubular endoplasmic reticulum,and lysosomes.Using dual-mode correlated live-cell imaging for a prolonged period of time,we observed novel subcellular structures named dark-vacuole bodies,the majority of which originate from densely populated perinuclear regions,and intensively interact with organelles such as the mitochondria and the nuclear membrane before ultimately collapsing into the plasma membrane.This work demonstrates the unique capabilities of SR-FACT,which suggests its wide applicability in cell biology in general.

关键词： landscape illumination partner

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