IMPCs stained for markers of muscle stem, progenitor and differentiated cells. iMPCs recapitulate muscle differentiation in a dish. Credit: Ori Bar-Nur and Mattia Gerli
A team of scientists has created a simple and robust approach to directly reprogram mature skin cells into immature muscle cells in mice, a discovery that could someday yield regeneration of human muscle cells.
The researchers combined transient expression of a protein called MyoD with the treatment of three small molecules to convert mouse skin cells into induced myogenic progenitor cells (iMPCs), which propagate extensively and share 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,” senior study author Konrad Hochedlinger of Massachusetts General Hospital and the Harvard Stem Cell Institute, said in a statement. “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.”
Skeletal muscle is largely composed of differentiated, multinucleated myofibers responsible for contraction and movement. Muscle tissue contains a quiescent population of mononucleated stem cells termed satellite cells, which are located between the myofibers’ basal lamina and sarcolemma.
Scientists have previously developed protocols for generating muscle cells for disease modeling or tissue engineering that are limited. In addition, methods that convert embryonic or induced pluripotent stem cells into mature muscle cells come with a risk of tumor formation after transplantation.
In the new study, the researchers temporarily increased MyoD expression in mouse skin cells and then treated the cells with a GSK3β inhibitor, a TGF-β1 receptor inhibitor, and a cyclic AMP agonist, some of which have shown the ability to enhance cellular reprogramming.
This resulted in iMPCs that are capable of long-term self-renewal and large-scale expansion. They also expressed key molecular markers of satellite cells and myoblasts, as well as retained the ability to produce mature muscle fibers that expressed adult muscle markers and displayed vigorous contractions.
“Our ability to recapitulate muscle differentiation in a dish may reduce the need for animal models,” co-first author Ori Bar-Nur of Massachusetts General Hospital and Harvard University, said in a statement. “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.”
The next step will be for the team to compare in more detail the molecular and functional properties of iMPCs with muscle-derived satellite cells. They also plan to study the cellular reprogramming process at the molecular level and redefine the protocols to generate more homogenous populations of muscle stem and progenitor cells instead of mixtures containing mature muscle cells.
The researchers also need to test whether the approach could work with human cells, which could yield therapy and drug treatment options for those with muscular dystrophy.
“Patient-specific iMPCs could be used for personalized medicine by treating patients with their own genetically matched cells,” co-first author Mattia Gerli of Massachusetts General Hospital and Harvard Medical School, said in a statement. “If disease-causing mutations are known, as is the case in many muscular dystrophies, one could in principle repair the mutation in iMPCs prior to transplantation of the corrected cells back into the patient.”
The study was published in Stem Cell Reports.
