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Skeletal Muscle Regeneration from Pluripotent Stem Cells

多能干细胞的骨骼肌再生

基本信息

批准号：
10633107
负责人：
Rita C. R. Perlingeiro
金额：
$ 42.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633107
关键词：
Address Adult Bar Codes Biochemical Biological Assay CD34 gene Cell Compartmentation Cell Fraction Cell Transplantation Cells Cues Development Disease Embryo Endowment Engraftment Environment Exposure to Generations High-Throughput Nucleotide Sequencing Human In Vitro Injury Integrins Investigation Mesoderm Methods MicroRNAs Molecular Molecular Profiling Mononuclear Mus Muscle Myoblasts Natural regeneration Neonatal Outcome Pathway interactions Play Pluripotent Stem Cells Population Post-Transcriptional Regulation Process Proteins Regenerative Medicine Research Role Signal Pathway Signal Transduction Skeletal Muscle Somatic Cell Source Time Transplantation United States National Institutes of Health cell type donor stem cell fetal gain of function in vivo induced pluripotent stem cell loss of function muscle regeneration notch protein progenitor programs regeneration potential satellite cell self-renewal skeletal stem cells tool transcriptome virus genetics

项目摘要

Summary Pluripotent stem cells (ES and iPS cells) have the ability to self-renew and to differentiate into multiple lineages in vitro. This makes these cells a powerful tool to study early embryonic developmental pathways and to generate specific cell populations for regenerative medicine and disease investigation. Our research group has pioneered methods to derive large quantities of skeletal myogenic progenitor cells from mouse and human pluripotent ES and iPS cells. Upon transplantation into dystrophic mice, these progenitors are not only able to generate new functional myofibers, but also to seed the satellite cell compartment, thus providing long-term regeneration. With prior NIH support, we defined the molecular signature of in vitro-generated PSC-derived myogenic progenitors by comparing their transcriptome profiles to those of primary skeletal myogenic progenitors isolated at different developmental stages. Our findings revealed that PSC-derived myogenic progenitors possess a molecular signature similar to embryonic/fetal myoblasts. Paradoxically however, they differ functionally from fetal myoblasts, as PSC-derived myogenic progenitors show much superior myofiber engraftment and ability to seed the satellite cell niche, respond to multiple re-injuries and contribute to long-term regeneration. These results led us to hypothesize that exposure to the adult host skeletal muscle environment may induce molecular changes in transplanted cells. We found this to be the case as transcriptome analysis of PSC-derived mononuclear cells (MNCs) re-isolated after engraftment revealed a shift in molecular signature from embryonic/fetal towards neonatal/adult stages. In this renewal application we propose studies to understand i) the interaction and molecular cues provided by the adult niche that favor the in vivo maturation of PSC-derived myogenic progenitors, ii) the role of post-transcriptional regulation in this process, and iii) the dynamics of engraftment and the quiescence status of specific donor-derived sub-fractions.

概括多能干细胞（ES 和 iPS 细胞）具有自我更新和分化成多个谱系的能力体外。这使得这些细胞成为研究早期胚胎发育途径并产生用于再生医学和疾病研究的特定细胞群。我们的研究小组开创了从小鼠和人多能 ES 中获取大量骨骼肌原祖细胞的方法和 iPS 细胞。移植到营养不良小鼠后，这些祖细胞不仅能够产生新的功能性肌纤维，还可以播种卫星细胞室，从而提供长期再生。和在 NIH 支持之前，我们定义了体外生成的 PSC 衍生的肌源性祖细胞的分子特征通过将它们的转录组谱与在不同时间分离的原代骨骼肌原祖细胞的转录组谱进行比较发展阶段。我们的研究结果表明，PSC 衍生的肌源性祖细胞具有一种分子特征类似于胚胎/胎儿成肌细胞。然而矛盾的是，它们在功能上与胎儿不同成肌细胞，因为 PSC 衍生的肌原祖细胞表现出优异的肌纤维植入和播种能力卫星细胞生态位，对多次再损伤做出反应并有助于长期再生。这些结果导致我们假设暴露于成体宿主骨骼肌环境可能会引起分子变化在移植的细胞中。我们发现 PSC 衍生的单核细胞的转录组分析就是这种情况（跨国公司）植入后重新分离显示分子特征从胚胎/胎儿向新生儿/成人阶段。在此更新应用程序中，我们提出研究以了解 i) 相互作用和成体生态位提供的分子线索有利于 PSC 衍生的肌原细胞的体内成熟祖细胞，ii）转录后调控在此过程中的作用，以及iii）植入和移植的动态特定供体来源的亚组分的静止状态。