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single-nucleus RNA sequencing Reveals Cardiac Macrophage Landscape in Hypoplastic Left Heart Syndrome

Congenital Heart Disease 2024年第2期19卷 233-246页

作者： Xiaozhuo Xu Yilin Huang Xu Han First Clinical Medical College Afﬁliated Hospital of Nanjing University of Chinese MedicineNanjing210008China Department of Geriatrics Afﬁliated Hospital of Nanjing University of Chinese MedicineNanjing210029China

Background:Hypoplastic left heart syndrome(HLHS)is one of the most challenging congenital heart diseases in clinical treatment.In cardiac tissues,resident macrophages fulﬁll critical functions in maintaining a stable cardiac state and have strong regenerative capacity and organ speciﬁcity.However,the molecular mechanisms of macro-phages in HLHS remained unclear.Methods:single-nucleus RNA sequencing(snrna-seq)data of HLHS and healthy control(donors)samples obtained from the Gene Expression Omnibus(GEO)database were normalized and clustered using the Seurat package.The“FindMarkers”function was used to screen differentially expressed genes(DEGs)between the HLHS and donor groups and to analyze the functional enrichment of the set of genes of interest.Finally,cell-cell communication,pseudotime,and single-cell regulatory network inference and cluster-ing(SCENIC)analyses were used to study the mechanisms of macrophages in HLHS.Results:Based on the snrna-seq data of HLHS and donors,we identiﬁed a total of 9 cell clusters,among which the proportion of macrophages was signiﬁcantly less in the HLHS group than in the control group.Subdivision of macrophage subpopulations(Macrophages 1,2,and 3)showed that Macrophages 1 was mainly involved in nervous system development,angiogenesis,and apoptotic processes.In addition,analysis of communication between Macro-phages 1 and cardiomyocytes revealed that ligand-acceptor pairs such as GAS6/AXL,IL6,IGF1,THY1,and L1CAM were present only in the donor group.Finally,pesudotime and SCENIC analyses demonstrated that FOXO3 and ELF2 played a critical role for Macrophages 1 to maintain cardiac function in patients with HLHS.Conclusion:Our study improved the current understanding of the molecular mechanisms of macrophage devel-opment in HLHS,showing that manipulating the regulatory role of macrophages in the heart can be a novel treat-ment for HLHS.

关键词： Hypoplastic left heart syndrome single-nucleus RNA sequencing macrophage cellular subpopulation transcription factor

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Uncovering the prominent role of satellite cells in paravertebral muscle development and aging by single-nucleus RNA sequencing

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Genes & Diseases 2023年第6期10卷 2597-2613页

作者： Xin Qiu Hao-Yu Wang Zhen-Yu Yang Li-Ming Sun Shu-Nan Liu Chui-Qin Fan Feng Zhu Department of Spinal Surgery The University of Hong Kong-Shenzhen HospitalShenzhenGuangdong 518000China Department of Orthopedics and Traumatology Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SAR 999077China College of Life Sciences University of Chinese Academy of SciencesBeijing 100000China Lars Bolund Institute of Regenerative Medicine Qingdao-Europe Advanced Institute for Life SciencesBGI-QingdaoQingdaoShandong 266000China China Medical University ShenyangLiaoning 110000China Department of Plastic and Reconstructive Surgery Xijing HospitalForth Military Medical UniversityXi'anShaanxi 710000China

To uncover the role of satellite cells(SCs)in paravertebral muscle development and aging,we constructed a single-nucleus transcriptomic atlas of mouse paravertebral muscle across seven timepoints spanning the embryo(day 16.5)to old(month 24)stages.Eight cell types,including SCs,fast muscle cells,and slow muscle cells,were identified.An energy metabolism-related gene set,TCA CYCLE IN SENESCENCE,was enriched in SCs.Forty-two skeletal muscle disease-related genes were highly expressed in SCs and exhibited similar expression patterns.Among them,Pdha1 was the core gene in the TCA CYCLE IN SENESCENCE;Pgam2,Sod1,and Suclg1 are transcription factors closely associated with skeletal muscle energy metabolism.Transcription factor enrichment analysis of the 42 genes revealed that Myod1 and Mef2a were also highly expressed in SCs,which regulated Pdha1 expression and were associated with skeletal muscle development.These findings hint that energy metabolism may be pivotal in SCs development and aging.Three ligand-receptor pairs of extracellular matrix(ECM)-receptor interactions,Lamc1-Dag1,Lama2-Dag1,and Hspg2-Dag1,may play a vital role in SCs interactions with slow/fast muscle cells and SCs self-renewal.Finally,we built the first database of a skeletal muscle single-cell transcriptome,the Musculoskeletal Cell Atlas(http://www.***.tech),which lists 630,040 skeletal muscle cells and provides interactive visualization,a useful resource for revealing skeletal muscle cellular heterogeneity during development and aging.Our study could provide new targets and ideas for developing drugs to inhibit skeletal muscle aging and treat skeletal muscle diseases.

关键词： Niche Paraspinal muscle Satellite cells Senescence single-nucleus RNA sequencing

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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 diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,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 cells.Upon 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 aging.In 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 senescence.This 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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single-nucleus transcriptomic profiling of multiple organs in a rhesus macaque model of SARS-CoV-2 infection

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Zoological Research 2022年第6期43卷 1041-1062页

作者： Qiang Ma Wenji Ma Tian-Zhang Song Zhaobo Wu Zeyuan Liu Zhenxiang Hu Jian-Bao Han Ling Xu Bo Zeng Bosong Wang Yinuo Sun Dan-Dan Yu Qian Wu Yong-Gang Yao Yong-Tang Zheng Xiaoqun Wang State Key Laboratory of Brain and Cognitive Science Institute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China Kunming National High-Level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China National Resource Center for Non-Human Primates National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China LivzonBio Inc.ZhuhaiGuangdong 519045China State Key Laboratory of Cognitive Neuroscience and Learning Beijing Normal UniversityBeijing 100875China IDG/McGovern Institute for Brain Research Beijing Normal UniversityBeijing 100875China Advanced Innovation Center for Human Brain Protection Beijing Institute for Brain DisordersCapital Medical UniversityBeijing 100069China

Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.

关键词： SARS-CoV-2 Rhesus macaque Animal model single-nucleus RNA sequencing Antiviral immune defects Multiple organs

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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 infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-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 continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,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 spermatogenesis.Collectively,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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single-nucleus profiling unveils a geroprotective role of the Foxo3 in primate skeletal muscle aging

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Protein & Cell 2023年第7期14卷 499-514页

作者： Ying Jing Yuesheng Zuo Yang Yu Liang Sun Zhengrong Yu Shuai Ma Qian Zhao Guoqiang Sun Huifang Hu Jingyi Li Daoyuan Huang Lixiao Liu Jiaming Li Zijuan Xin Haoyan Huang Juan Carlos Izpisua Belmonte Weiqi Zhang Si Wang Jing Qu Guang-Hui Liu 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 Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China China National Center for Bioinformation Beijing 100101China Aging Translational Medicine Center Intemational Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China Department of Obstetrics and Gynecology Center for Reproductive MedicinePeking University Third HospitalBeijing 100191China The Key Laboratory of Geriatrics Beijing Institute of GeriatricsInstitute of Geriatric MedicineChinese Academy of Medical SciencesBeijing Hospital/National Center of Gerontology of National Health CommissionBeijing 100730China Clinical Stem Cell Research Center Peking University Third HospitalBeijing 100191China Department of Orthopaedics Peking University First HospitalBeijing 100034China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish Center for Education and Research Beijing 101408China Altos Labs Inc.San DiegoCA 94022USA The Fifth People's Hospital of Chongqing Chongqing 400062China

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging.A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types,indicating a higher susceptibility of skeletal muscle fiber to aging.We found a downregulation of Foxo3 in aged primate skeletal muscle,and identi-fied FOxo3 as a hub transcription factor maintaining skeletal muscle homeostasis.Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model,we revealed that silence of Foxo3 accelerates human myotube senescence,whereas genetic activation of endogenous FOxO3 alleviates human myotube aging.Altogether,based on a combination of monkey skeletal muscle and human myotube aging research models,we unraveled the pivotal role of the FOxO3 in safeguarding primate skeletal muscle from aging,providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-relateddisorders.

关键词： single-nucleus RNA sequencing primate aging skeletal muscle FOxO3

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A single-nucleus transcriptomic atlas of the dog hippocampus reveals the potential relationship between specific cell types and domestication

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National Science Review 2022年第11期9卷 108-120页

作者： Qi-Jun Zhou Xingyan Liu Longlong Zhang Rong Wang Tingting Yin Xiaolu Li Guimei Li Yuqi He Zhaoli Ding Pengcheng Ma Shi-Zhi Wang Bingyu Mao Shihua Zhang Guo-Dong Wang State Key Laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of Sciences NCMIS CEMS RCSDSAcademy of Mathematics and Systems ScienceChinese Academy of Sciences School of Mathematical Sciences University of Chinese Academy of Sciences Kunming College of Life Science University of Chinese Academy of Sciences College of Life Science University of Chinese Academy of Sciences Genomic Center of Biodiversity Kunming Institute of ZoologyChinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of Sciences

The process of domestication has led to dramatic differences in behavioral traits between domestic dogs and gray wolves. Whole-genome research found that a class of putative positively selected genes were related to various aspects of learning and memory, such as long-term potentiation and long-term depression. In this study, we constructed a single-nucleus transcriptomic atlas of the dog hippocampus to illustrate its cell types, cell lineage and molecular features. Using the transcriptomes of 105 057 nuclei from the hippocampus of a Beagle dog, we identified 26 cell clusters and a putative trajectory of oligodendrocyte development.Comparative analysis revealed a significant convergence between dog differentially expressed genes(DEGs) and putative positively selected genes(PSGs). Forty putative PSGs were DEGs in glutamatergic neurons, especially in Cluster 14, which is related to the regulation of nervous system development. In summary, this study provides a blueprint to understand the cellular mechanism of dog domestication.

关键词： dog single-nucleus RNA sequencing hippocampus domestication

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