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

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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CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang jinghui lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation Centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational MedicineCenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining ***,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and *** this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome *** all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to *** investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC ***,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays *** work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

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Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

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Science China(Life Sciences) 2012年第8期55卷 699-708页

作者： LI Yue WU Liang lei jinghui ZHU Cheng WANG HongMei YU XiaoGuang LIN HaiYan Department of Biochemistry and Molecular Biology College of Basic Medical ScienceHarbin Medical UniversityHarbin 150081China State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China

Corticosteroid-binding globulin(CBG) is a high-affinity plasma protein that transports glucocorticoids and *** and we have reported non-synonymous single nucleotide polymorphisms(SNPs) that influence CBG production or steroid-binding ***,no promoter polymorphisms affecting the transcription of human CBG gene(Cbg) have been *** the present study we investigated function implications of six promoter SNPs,including 26 C/G,54 C/T,144 G/C,161 A/G,205 C/A,and 443/444 AG/,five of which are located within the first 205 base pairs of 5'-flanking region and close to the highly conserved footprinted elements,TATA-box,or *** reporter assays demonstrated that basal activity of the promoter carrying 54 T or 161 G was significantly *** first three polymorphisms,26 C/G,54 C/T,and 144 G/C located close to the putative hepatic nuclear factor(HNF) 1 binding elements,altered the transactivation effect of *** also found a negative promoter response to dexamethasone-activated glucocorticoid receptor(GR),although none of the SNPs affected its transrepression *** results suggest that human Cbg 26 C/G,54 C/T,144 G/C,and 161 A/G promoter polymorphisms alter transcriptional activity,and further studies are awaited to explore their association with physiological and pathological conditions.

关键词： corticosteroid-binding globulin single nucleotide polymorphism hepatic nuclear factor 1

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Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

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Protein & Cell 2018年第4期9卷 333-350页

作者： Zeming Wu Weiqi Zhang Moshi Song Wei Wang Gang Wei Wei Li jinghui lei Yu Huang Yanmei Sang Piu Chan Chang Chen Jing Qu Keiichiro Suzuki Juan Carlos Izpisua Belmonte Guang-Hui Liu State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 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 National Clinical Research Center for Geriatric Disorders Xuanwu Hospital of Capital Medical University Beijing 100053 China State Key Laboratory of Biomembrane and Membrane Biotechnology Institute of Zoology Chinese Academy of SciencesBeijing 100101 China Key Laboratory of Computational Biology CAS-MPG Partner Institute for Computational Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China Department of Medical genetics School of Basic Medical Sciences Peking University Health Science Center Beijing100191 China Department of Pediatric Endocrinology and Genetic Metabolism Beijing Children's Hospital Capital Medical UniversityNational Center for Children's Health Beijing 100045 China Institute for Advanced Co-Creation Studies Osaka University Osaka 560-8531 Japan Graduate School of Engineering Science Osaka University Osaka 560-8531 Japan Gene Expression Laboratory Salk Institute for Biological Studies La Jolla 92037 USA Key Laboratory of Regenerative Medicine of Minist~ of Education Institute of Aging and Regenerative Medicine JinanUniversity Guangzhou 510632 China

progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

关键词： WRN lamin HGPS Werner syndrome,stem cell aging

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FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction

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Protein & Cell 2021年第2期12卷 145-151页

作者： jinghui lei Si Wang Wang Kang Qun Chu Zunpeng Liu Liang Sun Yun Ji Concepcion Rodriguez Esteban Yan Yao Juan Carlos Izpisua Belmonte Piu Chan Guang-Hui Liu Weiqi Zhang Moshi Song 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 Disease Genomics and Individualized Medicine Laboratory Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute of Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China The MOH Key Laboratory of Geriatrics Beijing HospitalNational Center of GerontologyBeijing 100730China Department of Cardiology Beijing Anzhen HospitalCapital Medical UniversityBeijing 100029China Gene Expression Laboratory Salk Institute for Biological StudiesLa Jolla 92037USA

Dear Editor,Myocardial infarction(MI)is the irreversible cardiomyocyte death resulting from prolonged oxygen deprivation due to obstructed blood supply(ischemia),leading to contractile dysfunction and cardiac *** recent decades,stem cell transplantation has been extensively investigated for the repair of injured heart in animal studies and clinical trials(Kanelidis et al.,2017;Gyongyosi et al.,2018).

关键词： al. infarction cardiac

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A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis

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Protein & Cell 2023年第12期14卷 888-907页

作者： Daoyuan Huang Yuesheng Zuo Chen Zhang Guoqiang Sun Ying Jing jinghui lei Shuai Ma Shuhui Sun Huifen Lu Yusheng Cai Weiqi Zhang Fei Gao Andy Peng Xiang Juan Carlos Izpisua Belmonte Guang-Hui Liu Jing Qu Si Wang Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing100053China State Key Laboratory of Stem Cell and Reproductive 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 Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China 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 Institute for Stemcell and Regeneration CAsBeijing100101China China National Center for Bioinformation Beijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China 11Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish Center for Education and Research Beijing 101408China Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue EngineeringMinistry of EducationSun Yat-sen UniversityGuangzhou510000China Department of Biochemistry Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510000China Altos Labs Inc.San DiegoCA 92121USA and Aging Biomarker Consortium China

The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with ***,the regulatory mechanism underlying primate testicular aging remains largely ***,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic ***-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential ***,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional ***,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for ***,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.

关键词： single-nucleus RNA sequencing primate testis aging WT1

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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 ***,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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神魔小说背后隐含的中西文化差异——以《魔戒》和《西游记》为例

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华东理工大学学报（社会科学版） 2006年第4期21卷 93-96页

作者：雷静辉华东理工大学人文科学研究院上海200237

《魔戒》融合了北欧神话和基督教宗教精神,《西游记》则是儒道佛精神交汇的经典之作。本文从世界起源、生命意识、善恶观念几个方面入手,比较两部神魔小说所反映的民族心理、思维方式的差异,得到这样的结论:西方文化呈现自然客体化、追... 详细信息

《魔戒》融合了北欧神话和基督教宗教精神,《西游记》则是儒道佛精神交汇的经典之作。本文从世界起源、生命意识、善恶观念几个方面入手,比较两部神魔小说所反映的民族心理、思维方式的差异,得到这样的结论:西方文化呈现自然客体化、追求合本质生存以及二元对立思维的特点;中国文化则体现出自然主体化、追求生命的无限延时性以及整体性思维的特点。

关键词：《魔戒》《西游记》中西方文化比较

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浅谈技防在某博物馆安防系统设计中的应用

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低压电器 2009年第16期 32-35页

作者：姚凌志陈向阳雷景惠郑州大学综合设计研究院河南郑州450002

以某地市级博物馆为例,从设计原则、设计依据、各防护区域设计、机房电源等几个方面,对技防在其安防系统设计中的应用进行了具体阐述。实践证明,技防在安防系统中有着重要的作用,可有效防范外来风险和入侵。

关键词：安防系统技防边界监视区防护区禁区

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近30年中国不同地区气温、降水量及对ENSO的响应

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热带地貌 2018年第2期39卷 12-19页

作者：雷璟晖黄春菊华南师范大学地理科学学院广州510631 中国地质大学(武汉)地球科学学院武汉430070

以黑龙江、青海、江苏、广东四省为主要研究区,利用752个气象观测站点记录的气温和年降水量,经过克里金插值后,得到了1986年6月—2016年5月(共360个月)我国气温降水的空间分布和变化趋势,尝试找到它们近30年对于厄尔尼诺-南方涛动(ENSO... 详细信息

以黑龙江、青海、江苏、广东四省为主要研究区,利用752个气象观测站点记录的气温和年降水量,经过克里金插值后,得到了1986年6月—2016年5月(共360个月)我国气温降水的空间分布和变化趋势,尝试找到它们近30年对于厄尔尼诺-南方涛动(ENSO)响应的不同,进而探索不同地区ENSO的滞后性.得出以下结论:①气候变暖的背景下,中国各地的平均气温均在升高,最明显的地区是青藏高原和长江中下游地区.从1986年到2015年,青海省、江苏省升温速率为0.055℃/a和0.031℃/a,而黑龙江省升温速率只有0.004℃/a.中国大陆年降水整体呈现增加的趋势,华南地区和青藏地区增加最快,其中广东省和青海省从1986年到2015年的年降水量每年分别增加了4.99 mm和1.90 mm;②在El Ni?o事件期间,黑龙江省气温对这一过程几乎无响应变化外,其余三省气温变化的先后顺序是:广东省、江苏省和青海省;从持续时间来看,从短到长分别是:江苏省、广东省和青海省;③近30年,广东省和青海省的降水对ENSO的响应无明显滞后,江苏省的降水对ENSO滞后期为2个月,黑龙江省的降水对ENSO的滞后期为6个月.

关键词： ENSO 气温降水克里金插值线性拟合

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