Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors

Abstract

Summary: Skeletal muscle harbors quiescent stem cells termed satellite cells and proliferative progenitors termed myoblasts, which play pivotal roles during muscle regeneration. However, current technology does not allow permanent capture of these cell populations in vitro. Here, we show that ectopic expression of the myogenic transcription factor MyoD, combined with exposure to small molecules, reprograms mouse fibroblasts into expandable induced myogenic progenitor cells (iMPCs). iMPCs express key skeletal muscle stem and progenitor cell markers including Pax7 and Myf5 and give rise to dystrophin-expressing myofibers upon transplantation in vivo. Notably, a subset of transplanted iMPCs maintain Pax7 expression and sustain serial regenerative responses. Similar to satellite cells, iMPCs originate from Pax7+ cells and require Pax7 itself for maintenance. Finally, we show that myogenic progenitor cell lines can be established from muscle tissue following small-molecule exposure alone. This study thus reports on a robust approach to derive expandable myogenic stem/progenitor-like cells from multiple cell types. : In this article, Hochedlinger and colleagues reprogrammed mouse fibroblasts into induced myogenic progenitors (iMPCs) by transient expression of MyoD and treatment with small molecules. iMPCs can be extensively propagated in vitro and exhibit skeletal muscle stem/progenitor cell characteristics, including the requirement for Pax7 function as well as the ability to sustain muscle regeneration upon repeated injury. Keywords: skeletal muscle, satellite cells, direct lineage reprogramming, induced muscle progenitor cells, MyoD, Pax7, small molecules, transplantation, muscular dystrophy