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A human circulating immune cell landscape in aging and COVID-19

Protein & Cell 2020年第10期11卷 740-770页

作者： Yingfeng Zheng Xiuxing Liu Wenqing Le Lihui Xie He Li Wen Wen Si Wang Shuai Ma Zhaohao Huang Jinguo Ye Wen Shi Yanxia Ye Zunpeng Liu Moshi Song Weiqi Zhang Jing-Dong J.Han juan carlos lzpisua belmonte Chuanle Xiao Jing Qu Hongyang Wang Guang-Hui Liu Wenru Su State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeiing 100101China National Center for Liver Cancer Second Military Medical UniversityShanghai 200433China Department of Critical Care Wuhan Hankou HospitalWuhan 430012China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBejjing 100101China University of Chinese Academy of Sciences Beijing 100049China 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 Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesCenter for Quantitative Biology(CQB)Peking UniversityBeijing 100871China Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCAUSA

Age-associated changes in immune cells have been linked to an increased risk for ***,a global and detailed characterization of the changes that human circulating immune cells undergo with age is ***,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with *** found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic *** addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with ***,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular ***,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.

关键词： aging single-cell sequencing blood COVID-19 immune cells

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The labyrinth of nuclear reprogramming

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Journal of Molecular Cell Biology 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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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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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.

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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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Opening up the black box of human cell plasticity

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The Innovation 2022年第5期3卷 13-14页

作者： Yusheng Cai juan carlos Izpisua belmonte Jing Qu Guang-Hui Liu Weiqi Zhang 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 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 Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China China National Center for Bioinformation Beijing 100101China Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCA 92037USA Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China

Cell plasticity represents the ability of cells to acquire new *** plasticity can be reset in somatic cells via cellular reprogramming,a process that occurs in ***,cell plasticity occurs rarely in ***,Guan et *** cell plasticity in mature human cells,which they found to be essential for reprogramming human somatic cells to pluripotent stem cells using only small *** the first study demonstrates that chemical compounds can completely reprogram human somatic cells to a pluripotent state,it is a paradigm shift in developing pharmacological or therapeutic reprogramming approaches to control human cells.

关键词： al. plasticity programming

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无模型控制算法及其应用研究

无模型控制算法及其应用研究

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作者： juan carlos belmonte Herrera 北京交通大学

学位级别：硕士

In cases where the model of plants is complex or varying in time, certain parameters need to be experimentally determined;doing these experiments we have a valuable tool for understanding the behavior of the plant. The behavior of a dynamic system can be understood throw the utilization of techniques as analytical model （from the basis principles of physics）, with direct measure of many parameters of the plant with an identification of models from inputs and outputs. A procedure of modeling needs many interactions. Additional, acceptable control project needs the validation of the model. Examples of complex plants are iron ovens and helicopter rotors. Example of variant time plants is satellites that change their temperature when they are in orbit. A pendulum is an example of plant that can be modeling for basic principles. The most popular method is identifying of model plant using the experimental data, and then designing the control process. An engineer usually realizes certain numbers of experiments and uses them with many optimization techniques to build a model plant. The plant model is then used for designing model-based controllers. The methods that use experimental data can be divided on four categories:Indirect Control Project, Direct Control Project, Indirect Adaptive, and Direct Adaptive. The techniques are differentiated by operating offline and online and if the plant model is used directly or indirectly in the control of the project. When the project based on the plant model is used online is usually referred to as indirect adaptive control. The technique typically begins by assuming a nominal model for the plant. When new data are collected, the output is compared with the planned output for the plant model producing a nominal error. The gradient of the error with respect to the parameters of the plant is used to modify the parameters of the plant to improve the plant model. Periodically the control law is updated using the latest model obtained.

关键词：非线性系统自适应控制计算机技术控制算法

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A single-cell transcriptomic atlas of primate pancreatic islet aging

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National Science Review 2021年第2期8卷 17-31页

作者： Jingyi Li Yuxuan Zheng Pengze Yan Moshi Song Si Wang Liang Sun Zunpeng Liu Shuai Ma juan carlos Izpisua belmonte Piu Chan Qi Zhou Weiqi Zhang Guang-Hui Liu Fuchou Tang Jing Qu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of Sciences National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of Sciences Beijing Institute for Brain Disorders Advanced Innovation Center for Human Brain ProtectionNational Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University University of Chinese Academy of Sciences Beijing Advanced Innovation Center for Genomics Biomedical Pioneering Innovation CenterCollege of Life SciencesPeking University Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking University Institute for Stem Cell and Regeneration Chinese Academy of Sciences The MOH Key Laboratory of Geriatrics Beijing HospitalNational Center of Gerontology State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of Sciences Gene Expression Laboratory Salk Institute for Biological Studies CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences China National Center for Bioinformation

Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and *** cells age heterogeneously, complicating the efforts to unravel the molecular drivers underlying endocrine aging. To overcome these obstacles, we undertook single-cell RNA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased transcriptional variations, aged β-cells showed increased unfolded protein response(UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical ATF6 and IRE1 signaling pathways, comprising adaptive UPR during pancreatic aging. Notably, we found aging-related β-cell-specific upregulation of HSP90 B1, an endoplasmic reticulum-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis,suggesting an avenue to delaying β-cell aging and preventing aging-related diabetes.

关键词： islet β-cell aging single-cell RNA sequencing primate

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