A simple and robust approach for directly reprogramming mature skin cells into immature muscle cells has been developed. By combining transient expression of a protein called MyoD and treatment with three small molecules, researchers converted mouse skin cells into induced myogenic progenitor cells (iMPCs). These cells propagated extensively and shared key molecular and functional properties with skeletal muscle stem cells.
"Our study reports for the first time on the direct conversion of skin cells into expandable, functional muscle progenitors," says senior study author Konrad Hochedlinger of Massachusetts General Hospital and the Harvard Stem Cell Institute. "The prospect that iMPCs could be in principle derived from human skin cells has potential relevance for the study and treatment of human muscle conditions such as muscular dystrophies."
Previously developed protocols for generating muscle cells for disease modeling or tissue engineering have several limitations according to the team. For example, it has been notoriously difficult to maintain regeneration-promoting muscle stem and progenitor cells, known as satellite cells and myoblasts, for long periods of time in culture without losing proliferative and engraftment potential.
In the new study, published today in Stem Cell Reports, Hochedlinger and his team overcame previous limitations by temporarily increasing MyoD expression in mouse skin cells, and then treating these cells with three small molecules (i.e., a GSK3β inhibitor, a TGF-β1 receptor inhibitor, and a cyclic AMP agonist), some of which were previously shown to enhance cellular reprogramming.
The resulting iMPCs were capable of long-term self-renewal and large-scale expansion, and they expressed key molecular markers of satellite cells and myoblasts. In addition, iMPCs retained the ability to produce mature muscle fibers that expressed adult muscle markers and displayed vigorous contractions. Moreover, transplanted iMPCs gave rise to muscle fibers that sustained tissue regeneration in mice with leg injuries.
"Our ability to recapitulate muscle differentiation in a dish may reduce the need for animal models," says co-first author Ori Bar-Nur of Massachusetts General Hospital and Harvard University. "Our iMPC cultures share several important characteristics with bona fide muscle stem and progenitor cells, but we do not yet know whether these cell populations are indeed equivalent."
Image: iMPCs stained for markers of muscle stem, progenitor and differentiated cells. iMPCs recapitulate muscle differentiation in a dish. Image courtesy of Ori Bar-Nur and Mattia Gerli.