Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells
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RESEARCH
Open Access
Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells Sean M. Buchanan1† , Feodor D. Price1†, Alessandra Castiglioni1,2†, Amanda Wagner Gee1, Joel Schneider1, Mark N. Matyas1, Monica Hayhurst1, Mohammadsharif Tabebordbar1, Amy J. Wagers1 and Lee L. Rubin1*
Abstract Satellite cells are the canonical muscle stem cells that regenerate damaged skeletal muscle. Loss of function of these cells has been linked to reduced muscle repair capacity and compromised muscle health in acute muscle injury and congenital neuromuscular diseases. To identify new pathways that can prevent loss of skeletal muscle function or enhance regenerative potential, we established an imaging-based screen capable of identifying small molecules that promote the expansion of freshly isolated satellite cells. We found several classes of receptor tyrosine kinase (RTK) inhibitors that increased freshly isolated satellite cell numbers in vitro. Further exploration of one of these compounds, the RTK inhibitor CEP-701 (also known as lestaurtinib), revealed potent activity on mouse satellite cells both in vitro and in vivo. This expansion potential was not seen upon exposure of proliferating committed myoblasts or non-myogenic fibroblasts to CEP-701. When delivered subcutaneously to acutely injured animals, CEP-701 increased both the total number of satellite cells and the rate of muscle repair, as revealed by an increased cross-sectional area of regenerating fibers. Moreover, freshly isolated satellite cells expanded ex vivo in the presence of CEP-701 displayed enhanced muscle engraftment potential upon in vivo transplantation. We provide compelling evidence that certain RTKs, and in particular RET, regulate satellite cell expansion during muscle regeneration. This study demonstrates the power of small molecule screens of even rare adult stem cell populations for identifying stem cell-targeting compounds with therapeutic potential. Keywords: Satellite cells, Screening, RET, GDNF, Lestaurtinib, CEP-701
Background Satellite cells are the adult stem cells of skeletal muscle and support postnatal muscle growth and repair. In adult muscle, satellite cells are, for the most part, mitotically quiescent and reside between the basal lamina and sarcolemma of the muscle fiber [1–3]. Satellite cells can both differentiate and self-renew, and these * Correspondence: [email protected] † Sean M. Buchanan, Feodor D. Price and Alessandra Castiglioni contributed equally to this work. 1 Harvard University Department of Stem Cell and Regenerative Biology, 7 Divinity Ave, Cambridge, MA 02138, USA Full list of author information is available at the end of the article
characteristics allow adult skeletal muscle to regenerate repeatedly in the face of muscle damage [4–6]. Following acute injury, satellite cells exit quiescence and give rise to a transit-amplifying population of myogenic progenitors termed myoblasts [7, 8]. The capacity of the skeletal muscle to grow and regenerate is also required during postnatal g
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