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MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer

Research 2024年第2期2023卷 239-257页

作者： Cui Wang Kuan Yang Xiaoqian Liu Si Wang Moshi Song juan carlos izpisua Belimonte Jing Qu Guang-Hui Liu Weiqi Zhang CAS Key Laboratory of Genomic and Precision Medicine Beijng 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 State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Bejing 100101China 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 Altos Labs Inc.San DiegoCA 94022USA

Mitochondrial dysfunction is a hallmark feature of cellular senescence and organ ***,we asked whether the mitochondrial antiviral signaling protein(MAVS),which is essential for driving antiviral response,also regulates human stem cell *** answer this question,we used CRISPR/Cas9-mediated gene editing and directed differentiation techniques to generate various MAVS-knockout human stem cell *** found that human mesenchymal stem cells(hMSCs)were sensitive to MAVS deficiency,as manifested by accelerated senescence *** uncovered that the role of MAVS in maintaining mitochondrial structural integrity and functional homeostasis depends on its interaction with the guanosine triphosphatase optic atrophy type 1(OPA1).Depletion of MAVS or OPA1 led to the dysfunction of mitochondria and cellular senescence,whereas replenishment of MAVS or OPA1 in MAVS-knockout hMSCs alleviated mitochondrial defects and premature senescence *** together,our data underscore an uncanonical role of MAVS in safeguarding mitochondrial homeostasis and antagonizing human stem cell senescence.

关键词： CRISPR/Cas9 homeostasis Mitochondrial

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Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

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Protein & Cell 2024年第1期15卷 36-51页

作者： Jinghui Lei Xiaoyu Jiang Daoyuan Huang Ying Jing Shanshan Yang Lingling Geng Yupeng Yan Fangshuo Zheng Fang Cheng Weiqi Zhang juan carlos izpisua belmonte Guang-Hui Liu Si Wang Jing Qu 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 Intermational Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China National Laboratory of Biomacromolecules CAs Center for Excellence in BiomacromoleculesInstitute of BiophysicsBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish Center for Education and Research Beijing 101408China Aging Biomarker Consortium China Altos Labs San DiegoCA 92121United State

Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological ***,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely ***,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response *** comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular *** found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic ***,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

关键词： HIF-1 human ESC vascular cell regeneration

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A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai Ma Si Wang juan carlos izpisua belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China 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 Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related ***,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely ***,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche *** in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during *** particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular *** study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RNA sequencing liver hepatocytes aging senescence SREBP2

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The labyrinth of nuclear reprogramming

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分子细胞生物学报:英文版 2011年第6期3卷 327-329页

作者： Ignacio Sancho-Martinez Emmanuel Nivet juan carlos izpisua belmonte Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Center for Regenerative Medicine in Barcelona Dr Aiguader 88Barcelona 08003Spain

Human embryonic stem cells(ESCs)have the capability to differentiate into all somatic cell types,a process that recapitu-lates the early stages of human ***,the use of ESCs raises several controversies,particularly concern-ing the ethical dilemma regarding the use of human embryonic material and the need for embryo *** discov-ery of induced pluripotent stem cell(iPSC)technology in 2006(Takahashi and Yamanaka,2006)opened the door for possible application of pluripotent stem-cell-related therapies in the clinic as well as for the generation of patient-derived pluripotent stem cells suitable for disease modeling in vitro.

关键词： programming destruction opened

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Adenine base editing disease mutations in to mimic or correcl rodents

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Protein & Cell 2018年第9期9卷 752-753页

作者： Ruotong Ren juan carlos izpisua belmonte Guang-Hui Liu Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric Disorders Xuanwu Hospital of Capital Medical University Beijing 100053 China National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Gene Expression Laboratory Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla California 92037 USA Institute of Stem cell and Regeneration Chinese Academy of Sciences Beijing 100101 China

Cytidine base editors （CBEs, rAPOBECI-nCas9-UGI） and adenine base editors （ABEs, TadA-TadA＊-nCas9） are newly developed genome-editing tools that have enabled highly efficient base conversions （CoG to T·A or A·T to G·C） at designated target sites （Komor et al., 2016; Gaudelli et al., 2017）. Both types of base editors enzymatically catalyze deamination of target bases and respectively replace C with U or A with I.

关键词： Basic Editing Adenine Base GSD II Hereditary Tyrosinemia Type Target Site Identification

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Human induced pluripotent stem cells derived hepatocytes:rising promise for disease modeling,drug development and cell therapy

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Protein & Cell 2012年第4期3卷 246-250页

作者： Fei Yi Guang-Hui Liu juan carlos izpisua belmonte Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCA 92037USA Center for Regenerative Medicine in Barcelona 08003 BarcelonaSpain National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug *** hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development *** this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.

关键词： induced pluripotent stem cells hepatocytes disease modeling drug development cell therapy

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First progeria monkey model generated using base editor

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Protein & Cell 2020年第12期11卷 862-865页

作者： Pradeep Reddy Yanjiao Shao Reyna Hernandez-Benitez Estrella Nunez Delicado juan carlos izpisua belmonte Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Universidad Catolica San Antonio de Murcia(UCAM) Campus de los JerdnimosN°13512Guadalupe 30107Spain

In this issue,Wang et *** on the generation of a nonhuman primate model of Hutchinson-Gilford progeria syndrome(HGPS)using a base *** editing is an emerging novel genome editing technique for modifying a single base pair at specific sites in the *** editors(BEs)have two prin cipal comp orients,a catalytically in active or single strand cleaving Cas-variant,which binds to the guide RNA and a nucleobase deaminase domain to convert specific base pairs at the target loci(Komor et al.,2016;Nishida et al.,2016;Gaudelli et al.,2017).Cytosine base editor(CBE)and adenine base editor(ABE)are two baseeditors,which con vert Cytosi ne-Gua nine(C-G)to Thymine-Adenine(T-A)and A-T to G-C,respectively.

关键词： base convert editor

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Establishment of hepatic and neural differentiation platforms of Wilson’s disease specific induced pluripotent stem cells

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Protein & Cell 2012年第11期3卷 855-863页

作者： Fei Yi Jing Qu Mo Li Keiichiro Suzuki Na Young Kim Guang-Hui Liu juan carlos izpisua belmonte Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Center for Regenerative Medicine in Barcelona Dr.Aiguader 8808003 BarcelonaSpain

The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human ***’s disease(WD)is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B *** affects multiple organs with primary manifestations in the liver and central nervous system(CNS).In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes,we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural *** we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of *** with directed cell differentiation strategies,we successfully differentiated WD iPSC into hepatocyte-like cells,neural stem cells and *** expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated *** we established a platform for studying both hepatic and neural abnormalities of WD,which may provide a new tool for tissue-specific disease modeling and drug screening in the future.

关键词： induced pluripotent stem cell Wilson’s disease hepatocyte neural stem cell neuron

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Direct conversion of human fibroblasts into retinal pigment epithelium-like cells by defined factors

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Protein & Cell 2014年第1期5卷 48-58页

作者： Kejing Zhang Guang-Hui Liu Fei Yi Nuria Montserrat Tomoaki Hishida Concepcion Rodriguez Esteban juan carlos izpisua belmonte] Gene Expression Laboratory Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Department of Molecular and Cellular Physiology Stanford University School of Medicine 265 Campus Drive StanfordCA 94305 USA Center for Regenerative Medicine in Barcelona Dr. Aiguader 88 08003 Barcelona Spain Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN) BarcelonaSpain

The generation of functional retinal pigment epithelium （RPE） is of great therapeutic interest to the field of regenerative medicine and may provide possible cures for retinal degenerative diseases, including age-related macular degeneration （AMD）. Although RPE cells can be produced from either embryonic stem cells or induced pluripotent stem cells, direct cell reprogramming driven by lineage-determining transcription factors provides an immediate route to their generation. By monitoring a human RPE specific Bestl：：GFP reporter, we report the conversion of human fibroblasts into RPE lineage using defined sets of transcription factors. We found that Bestl：：GFP positive cells formed colonies and exhibited morphological and molecular features of early stage RPE cells. Moreover, they were able to obtain pigmen- tation upon activation of Retinoic acid （RA） and Sonic Hedgehog （SHH） signaling pathways. Our study not only established an ideal platform to investigate the tran- scriptional network regulating the RPE cell fate deter- mination, but also provided an alternative strategy to generate functional RPE cells that complement the useof pluripotent stem cells for disease modeling, drug screening, and cell therapy of retinal degeneration.

关键词： retinal pigment epithelium fibroblasts,direct conversion

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Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration

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Protein & Cell 2023年第6期14卷 398-415页

作者： Qian Zhao Yandong Zheng Dongxin Zhao Liyun Zhao Lingling Geng Shuai Ma Yusheng Cai Chengyu Liu Yupeng Yan juan carlos izpisua belmonte Si Wang Weiqi Zhang Guang-Hui Liu Jing Qu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuan Wu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China 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 Sciencesand China National Center for BioinformationBeijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China The Fifth People's Hospital of Chongqing Chongqing 400062China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China Altos Labs Inc.San DiegoCA 94022USA

Hair loss affects millions of people at some time in their life,and safe and efficient treatments for hair loss are a significant unmet medical *** report that topical delivery of quercetin(Que)stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in *** construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1αin endothelial *** administration of a HIF-1αagonist partially recapitulates the pro-angiogenesis and hair-growing effects of ***,these findings provide a molecular understanding for the efficacy of Que in hair regrowth,which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine,and suggest a route of pharmacological intervention that may promote hair regrowth.

关键词： single-cell RNA-sequencing Que hair follicle regeneration endothelial cells HIF-1α

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