Skeletal Muscle Regeneration from Differentiating Pluripotent Stem Cells

分化多能干细胞的骨骼肌再生

• 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
• 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

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）具有自我更新和在体外分化成多个谱系的能力。这使得这些细胞成为研究早期胚胎发育途径和为再生医学和疾病研究产生特定细胞群的有力工具。在R01 AR055299的支持下，我们的研究小组开创了从小鼠和人类多能ES和iPS细胞中获得骨骼肌细胞的方法。在我们的工作之前，这方面的研究很少，因为骨骼肌分化在体外分化过程中效率极低。我们认为