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: 9918609
• 负责人: April D Pyle
• 金额: $ 11.1万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918609
• 关键词: Aging; Antisense Oligonucleotides; Biology; Birth; Cachexia; Cell Compartmentation; Cell Differentiation process; Cell Line; Cell Therapy; Cell Transplantation; Cell Transplants; 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 body; Immune; In Vitro; Incidence; Instruction; Knowledge; Laboratories; Lead; Lentivirus Vector; Light; Location; Maintenance; Mediating; Mesoderm; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscular Atrophy; Muscular Dystrophies; Mutation; Myopathy; Nanostructures; PAX7 gene; Paraxial Mesoderm; Pathway interactions; Patients; Pattern; Population; Preclinical Testing; Progenitor Cell Engraftment; Reading Frames; Regenerative Medicine; Research; Role; SHH gene; Safety; Sampling; Screening procedure; Signal Transduction; Skeletal Muscle; Somatic Cell; Source; Specific qualifier value; Stem cells; System; Testing; Therapeutic; Therapeutic Intervention; To specify; Transplantation; Viral; Virus Diseases; Work; cell type; design; effective therapy; exon skipping; experimental study; genetic manipulation; human embryonic stem cell; human model; human pluripotent stem cell; improved; in vivo; induced pluripotent stem cell; male; mini-dystrophin; molecular recognition; mouse model; myogenesis; nanoparticle; novel; novel strategies; overexpression; pre-clinical; progenitor; recruit; regenerative; regenerative therapy; repaired; satellite cell; screening; self assembly; skeletal; skeletal muscle differentiation; small molecule; stem cell biology; tool; transcription factor; tumorigenic

PROJECT SUMMARY/ABSTRACT 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.

项目摘要/摘要 人类多能干细胞(HPSCs)在再生医学方面有着巨大的前景。 分化为来自所有三个胚胎生殖层的细胞。进一步的hPSC提供了独特的临床前 在患者样本中评估疾病机制和治疗方法的筛选工具。尽管有巨大的 HPSC的潜力，在干细胞用于基于细胞的治疗之前需要克服许多障碍 包括对调节人类骨骼肌的生长因子信号的不完全了解 祖细胞(SMPC)规格、生长和植入。在这项提案中，我们将研究细胞 胚胎发育过程中hPSCs决定骨骼肌命运所需的信号。我们还将 开发第一种筛选方法，以确定人类SMPC命运的新调控因素。当务之急是我们 了解如何在不进行遗传或病毒操作的情况下获得SmpC。作为另一种方法，我们有 开发了独特的非病毒重新编程平台，从而实现了卓越的交付和重新编程 效率，并将被用于在没有病毒或基因操作的情况下指定SMPC。我们将比较In 在DMD小鼠模型中，生长因子导向的和重新编程的SMPC的体内植入潜力。 指导SMPC命运的重编程策略的发展和调控信号的识别 肌祖细胞的规范和维护可以提高我们对人类骨骼的基本理解 以及增强我们从人类产生可伸缩的祖细胞治疗肌肉疾病的能力 包括DMD。