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Revealing muscle stem cell heterogeneity in mice and humans through deep single-cell analysis

通过深度单细胞分析揭示小鼠和人类肌肉干细胞异质性

基本信息

批准号：
10431836
负责人：
Benjamin David Cosgrove
金额：
$ 54.77万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431836
关键词：
Address Adult Affect Age Aged, 80 and over Aging Algorithms Antigens Atlases Biocompatible Materials Biological Assay Bioluminescence Biomedical Engineering Biopsy CDKN2A gene Cell Aging Cell Cycle Cells Clinical Communication Cues Data Defect Dependence Dimensions Disease Elderly Female Functional disorder Genes Health Heterogeneity Homeostasis Human Hydrogels Immunocompromised Host In Vitro Incidence Individual Inherited Injury Integral Membrane Protein Knockout Mice Libraries Life Link Maintenance Microfluidics Molecular Molecular Target Mus Muscle Muscle Cells Muscle function Muscle satellite cell Muscular Dystrophies Myoblasts Myopathy Natural regeneration Pathology Pathway interactions Patients Phenotype Population Proteins Quality of life Regenerative capacity Research Resected Resolution Role STAT3 gene Sampling Skeletal Muscle Surface Antigens System Testing Tissues Transplantation Trauma Traumatic injury aged base conditional knockout in vitro Assay in vivo inhibitor knock-down male mortality mouse model muscle aging muscle form muscle regeneration p38 Mitogen Activated Protein Kinase progenitor prospective reconstruction regeneration potential repair function repaired response to injury satellite cell self-renewal senescence single cell analysis single cell sequencing single-cell RNA sequencing stem stem cell population stem cell self renewal stem cells therapeutic development therapeutic target tool transcriptome young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Muscle stem cells (MuSCs), also known as satellite cells, are essential to skeletal muscle regeneration throughout life. In aged individuals, muscle mass and regenerative capacity after injury progressively decline, leading to diminished quality of life. We have recently demonstrated that MuSCs prospectively isolated from aged mice are highly heterogeneous and, as a population, have a marked reduction in regenerative capacity relative to young adult MuSCs, revealing a previously undetected intrinsic stem cell defect in aged MuSCs. The dysfunction of aged MuSCs is characterized by a shift from reversible quiescence to cellular senescence, driven by elevation of the p16Ink4a cell-cycle inhibitor, and inefficient self-renewal, caused by aberrant cell-autonomous activation of the p38 mitogen-activated protein kinase and STAT3 pathways. What causes these inherent alterations and how to prospectively identify and treat dysfunctional MuSCs in aged mice and humans remain unanswered questions. We propose to combine high-throughput deep single-cell RNA-sequencing across varied adult mouse and human muscle samples and stem-cell population reconstruction algorithms to identify cell- surface antigen profiles that unambiguously distinguish between health and diseased MuSCs in mouse and human aging. We hypothesize that this approach will enable discovery of heterogeneously expressed MuSC cell-surface antigens that demark differing stem-cell capacities within a new-found functional hierarchy. We will prospectively isolate and transplant mouse and human MuSCs sub-populations and perform limiting dilution transplantation assays and self-renewal assays using bioengineered culture microenvironments. We will perform conditional deletion and transient knockdown studies to investigate if the identified antigens have mechanistic roles in self-renewal dysfunction in vivo and in vitro. These proposed studies will provide a deeply-profiled organized cellular atlas of muscle stem and progenitor cells in mouse and human aging that should enable rational therapeutic development targeting dysregulated stem cells for enhancing muscle repair in the elderly following trauma.

项目总结/文摘