Skeletal Muscle Regeneration from Differentiating Pluripotent Stem Cells

分化多能干细胞的骨骼肌再生

基本信息

批准号：
8926353
负责人：
Rita C. R. Perlingeiro
金额：
$ 33.44万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8926353
关键词：
Adult Area Binding Biochemical Biological Models Cell Transplantation Cells Chromatin Complex Data Set Development Dextrans Disease Disease model Duchenne muscular dystrophy Dystrophin Embryo Engraftment Exercise Exposure to Generations Genes Genetic Genetic Transcription Goals Guide RNA Health Hereditary Disease Human In Vitro Injury Investigation Measures Mediating Mesoderm Methods Modeling Molecular Molecular Profiling Mus Muscle Muscle Development Muscle Fibers Myopathy Nature Neural tube Nucleic Acid Regulatory Sequences Paraxial Mesoderm Pathogenesis Pathology Pathway interactions Patients Pattern Permeability Pluripotent Stem Cells Population Process Recruitment Activity Regenerative Medicine Regulation Reporter Research Side Signal Transduction Site Skeletal Muscle Somatic Cell Somites Structure System Testing Therapeutic Time Work base cell type cofactor cohort embryonic stem cell human embryonic stem cell line in vitro Model in vivo induced pluripotent stem cell insight knock-down mini-dystrophin muscle regeneration myogenesis notochord development progenitor programs protein complex regenerative satellite cell self-renewal skeletal skeletal muscle differentiation tool uptake

Adult Area Binding Biochemical Biological Models Cell Transplantation Cells Chromatin Complex Data Set Development Dextrans Disease Disease model Duchenne muscular dystrophy Dystrophin Embryo Engraftment Exercise Exposure to Generations Genes Genetic Genetic Transcription Goals Guide RNA Health Hereditary Disease Human In Vitro Injury Investigation Measures Mediating Mesoderm Methods Modeling Molecular Molecular Profiling Mus Muscle Muscle Development Muscle Fibers Myopathy Nature Neural tube Nucleic Acid Regulatory Sequences Paraxial Mesoderm Pathogenesis Pathology Pathway interactions Patients Pattern Permeability Pluripotent Stem Cells Population Process Recruitment Activity Regenerative Medicine Regulation Reporter Research Side Signal Transduction Site Skeletal Muscle Somatic Cell Somites Structure System Testing Therapeutic Time Work base cell type cofactor cohort embryonic stem cell human embryonic stem cell line in vitro Model in vivo induced pluripotent stem cell insight knock-down mini-dystrophin muscle regeneration myogenesis notochord development progenitor programs protein complex regenerative satellite cell self-renewal skeletal skeletal muscle differentiation tool uptake

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项目摘要

DESCRIPTION (provided by applicant): 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 powerful tool to study early embryonic developmental pathways and to generate specific cell populations for regenerative medicine and disease investigation. Supported by R01 AR055299, our research group has pioneered methods to derive skeletal myogenic cells from mouse and human pluripotent ES and iPS cells. Until our work, studies in this area were rare since skeletal myogenic differentiation is extremely inefficient during in vitro differentiation. We reasoned that because in vitro systems do not recapitulate neural tube or notochord development, and indeed do not produce structures resembling somites, that the inducing signals that properly pattern paraxial mesoderm were absent. We have overcome this roadblock by activating the myogenic program through transient induction of Pax3 or Pax7 during early mesoderm development. This approach allows for the in vitro generation of large quantities of early embryonic skeletal myogenic progenitors. Transplantation of these cells into dystrophic mice results in myofiber and satellite cell engraftment that is accompanied by improvement in muscle force generation. This renewal application builds on the advances we have brought to the field over the past 5 years and evolves from these into 3 areas: i) understanding the molecular regulation of the embryonic myogenic program by Pax3, ii) investigating the long-term regenerative capacity of human pluripotent donor-derived satellite cells as well as their transcriptional profiling in comparison to in vitro generated myogenic progenitors, and iii) using myotubes from patient-specific pluripotent cells to biochemically and functionally model DMD/BMD pathology and its reversal by therapeutic delivery of dystrophin mini-genes.

描述（由申请人提供）：多能干细胞（ES和IPS细胞）具有自我更新并在体外分化为多个谱系的能力。这使这些细胞具有强大的工具来研究早期的胚胎发育途径并生成特定的细胞群来进行再生医学和疾病研究。在R01 AR055299的支持下，我们的研究小组采用了从小鼠和人类多能ES和IPS细胞中得出骨骼肌细胞的方法。在我们的工作之前，在该领域的研究很少，因为在体外分化过程中骨骼肌分化效率极低。我们认为这一点因为体外系统不会概括神经管或脊索发育，并且确实不会产生类似于情节的结构，因此缺乏适当模拟近地胚层的诱导信号。我们通过在中胚层发育期间通过对PAX3或PAX7的短暂诱导来激活肌源程序来克服这一障碍。这种方法允许体外生成大量早期胚胎骨骼肌祖细胞。将这些细胞移植到营养不良的小鼠中会导致肌纤维和卫星细胞植入，并伴随着肌肉力产生的改善。这种更新的应用是基于我们在过去的5年中带入该领域的进步，并将这些申请从这些方面发展为3个领域：i）理解PAX3的分子调节，PAX3，ii）研究人类多元化供体卫星细胞的长期再生能力，并研究了其在比较中，并在其转录的生成中进行了培训，并在Quartientien pription中使用了II，并在Quartipition中使用了II，并在Vetro中进行了培训，并在Vetro sentrientien pription Is and Introic sentory heentii sentory sentory sogen controcy y in comploty introk y in corbality sento sentory，从患者特异性多能细胞到生化和功能上DMD/BMD病理学的肌管及其通过治疗性肌营养不良蛋白迷你生成来逆转。