Myoregenerative Potential of ABCB5+ Progenitors

干细胞移植作为一种治疗人类遗传性疾病的策略前景看好，包括 肌肉营养不良症。这项建议旨在理解和解决基于细胞的 Duchenne肌营养不良症的治疗方法：干细胞分离、增殖和植入。 这一建议是基于最近对新型三磷酸腺苷结合盒转运体ABCB5的表征 P-糖蛋白，它标记肌肉和肌肉中表达干细胞表型的细胞亚群 皮肤，并作为膜电势祖细胞融合和结果的决定因素进行调节 差异化。初步研究表明，ABCB5前体细胞在体外具有肌源性潜能。具体的 本研究的目的是：1.明确ABCBS阳性祖细胞的生肌潜能 肌肉或皮肤与ABCBS阴性细胞群体的关系，并剖析ABCB5在调控中的作用 利用ABCB5特异性细胞分化和融合将肌祖细胞融合到多核肌管中 体外检测。2.鉴定与ABCBS阳性相关的分子调控网络 祖细胞的表型，并确定这种网络是否可以被特异性地调制来诱导 肌祖细胞的体外繁殖。3.研究异种或同种异体ABCBS阳性移植的能力 从人或小鼠肌肉或皮肤中分离肌祖细胞以恢复肌营养不良蛋白的表达 建立免疫缺陷的DMD小鼠模型(NOD/Rag1nullDMDmdx5cv)，并确定ABCB5在其中的作用 供体细胞融合到受体肌纤维中，从而在供体细胞植入和干细胞治疗中 功效。因此，该提案与旨在开发新的治疗方法的努力高度相关 Duchenne肌营养不良症和其他遗传性肌病。

Stem cell transplantation holds great promise as a therapeutic strategy in human genetic disorders, including muscular dystrophies. This proposal aims at understanding and addressing three major hurdles of cell-based therapeutic approaches to Duchenne muscular dystrophy: stem cell isolation, propagation and engraftment. The proposal is based on the recent characterization of the novel ATP-binding cassette transporter ABCB5 P-glycoprotein by the applicant, which marks stem cell phenotype-expressing cell subsets in muscle and skin, and regulates as a determinant of membrane potential progenitor cell fusion and resultant differentiation. Preliminary studies indicate a myogenic potential of ABCB5 progenitors in vitro. The specific aims of this study are 1. To define the myogenic potential of ABCBS-positiveprogenitors derived from muscle or skin vis-a-vis ABCBS-negative cell populations, and to dissect the role of ABCB5 in regulating myoprogenitor fusion into multinucleated myotubes using ABCB5-specific cell differentiation and fusion assays in vitro. 2. To identify the molecular regulatory networks associated with the ABCBS-positive progenitor phenotype and to determine whether such networks can be specifically modulated to induce in vitro myoprogenitor propagation. 3. To investigate the capacity of xeno- or allografted ABCBS-positive myoprogenitors isolated from human or murine muscle or skin to restore dystrophin expression in an immunodeficient mouse model of DMD (NOD/Rag1nullDMDmdx5cv) in vivo, and define the role of ABCB5 in donor cell fusion into recipient myofibers, and hence in donor cell engraftment and stem cell therapeutic efficacy. Thus, the proposal is highly relevant to efforts directed at developing novel therapeutic approaches to Duchenne muscular dystrophy and other inherited myopathies.