Reprogramming and Directed Differentiation of Skeletal Muscle Cells from hPSCs.

hPSC 中骨骼肌细胞的重编程和定向分化。

• 批准号: 8737009
• 负责人: April D Pyle
• 金额: $ 32.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737009
• 关键词: Aging; Antisense Oligonucleotides; Biology; Birth; Cachexia; Cell Differentiation process; Cell Line; Cell Therapy; Cell Transplantation; Cells; Childhood; Clinical Trials; Cues; Cyclic GMP; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Embryo; Embryonic Development; Engraftment; Evaluation; Foundations; Future; Genetic; Genome; Germ Layers; Goals; Grant; Growth; Growth Factor; Human; Human Development; Human body; Immune; In Vitro; Incidence; Knowledge; Laboratories; Lead; Lentivirus Vector; Life; Light; Location; Maintenance; Mediating; Mesoderm; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscular Dystrophies; Mutation; Myopathy; PAX7 gene; Paraxial Mesoderm; Pathway interactions; Patients; Pattern; Pluripotent Stem Cells; Population; Progenitor Cell Engraftment; Reading Frames; Recruitment Activity; Regenerative Medicine; Research; Role; SHH gene; Safety; Sampling; Signal Transduction; Skeletal Muscle; Somatic Cell; Source; Specific qualifier value; Stem cells; System; Testing; Therapeutic; Therapeutic Intervention; Time; To specify; Transplantation; Viral; Virus Diseases; Work; cell growth; cell type; design; effective therapy; exon skipping; genetic manipulation; human embryonic stem cell; improved; in vivo; induced pluripotent stem cell; male; mini-dystrophin; molecular recognition; mouse model; myogenesis; nanoparticle; nanostructured; novel; novel strategies; overexpression; pre-clinical; progenitor; public health relevance; regenerative; regenerative therapy; repaired; research clinical testing; research study; satellite cell; screening; self assembly; skeletal; skeletal muscle differentiation; small molecule; stem cell biology; tool; transcription factor; tumorigenic; wasting

DESCRIPTION (provided by applicant): Human pluripotent stem cells (hPSCs) have enormous promise for regenerative medicine as they can differentiate into cells from all three embryonic germ layers. Further hPSCs provide a unique pre-clinical screening tool for evaluating disease mechanisms and therapies in patient samples. Despite the enormous potential of hPSC, many obstacles need to be overcome before the use of stem cells in cell-based therapy will be realized, including an incomplete knowledge of the growth factor cues regulating human skeletal muscle progenitor cell (SMPC) specification, growth and engraftment. In this proposal we will investigate the cellular cues required to direct skeletal muscle fate from hPSCs as seen during embryonic development. We will also develop the first screening approach to identify new regulators of human SMPC fate. It is imperative that we understand how to obtain SMPCs without genetic or viral manipulation. As an alternative approach we have developed a unique non-viral reprogramming platform, which results in superior delivery and reprogramming efficiency, and will be utilized to specify SMPCs without viral or genetic manipulation. We will compare the in vivo engraftment potential of growth factor directed versus reprogrammed SMPCs in a mouse model of DMD. The development of reprogramming strategies to direct SMPC fate and the identification of signals regulating muscle progenitor cell specification and maintenance could improve our basic understanding of human skeletal myogenesis as well as enhance our ability to generate scalable progenitors from humans for muscle disorders including DMD.

描述(申请人提供)：人类多能干细胞(HPSCs)具有巨大的再生医学前景，因为它们可以分化为来自所有三个胚胎生殖层的细胞。此外，hPSC提供了一种独特的临床前筛查工具，用于评估患者样本的疾病机制和治疗方法。尽管hPSC具有巨大的潜力，但在将干细胞用于基于细胞的治疗之前，需要克服许多障碍，包括对调控人骨骼肌祖细胞(SMPC)规格、生长和植入的生长因子信号的不完全了解。在这项提案中，我们将研究指导骨骼肌命运所需的细胞线索 胚胎发育过程中的hPSCs。我们还将开发第一种筛选方法，以确定人类SMPC命运的新调节因子。我们必须了解如何在不进行基因或病毒操作的情况下获得SMPC。作为一种替代方法，我们开发了一种独特的非病毒重编程平台，该平台具有卓越的交付和重编程效率，并将用于指定SMPC，而无需病毒或基因操作。我们将在DMD的小鼠模型中比较生长因子定向的和重新编程的SMPC在体内的植入潜力。指导SMPC命运的重编程策略的发展以及调控肌祖细胞规范和维持的信号的识别可以提高我们对人类骨骼肌发生的基本理解，并增强我们为包括DMD在内的肌肉疾病从人类产生可伸缩的祖细胞的能力。