Hedgehog-driven myogenic tumors recapitulate skeletal muscle cellular heterogeneity
- Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138 (United States)
- Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 (United States)
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605 (United States)
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089 (United States)
Hedgehog (Hh) pathway activation in R26-SmoM2;CAGGS-CreER mice, which carry a tamoxifen-inducible activated Smoothened allele (SmoM2), results in numerous microscopic tumor foci in mouse skeletal muscle. These tumors exhibit a highly differentiated myogenic phenotype and resemble human fetal rhabdomyomas. This study sought to apply previously established strategies to isolate lineally distinct populations of normal mouse myofiber-associated cells in order to examine cellular heterogeneity in SmoM2 tumors. We demonstrate that established SmoM2 tumors are composed of cells expressing myogenic, adipocytic and hematopoietic lineage markers and differentiation capacity. SmoM2 tumors thus recapitulate the phenotypic and functional hetereogeneity observed in normal mouse skeletal muscle. SmoM2 tumors also contain an expanded population of PAX7+ and MyoD+ satellite-like cells with extremely low clonogenic activity. Selective activation of Hh signaling in freshly isolated muscle satellite cells enhanced terminal myogenic differentiation without stimulating proliferation. Our findings support the conclusion that SmoM2 tumors represent an aberrant skeletal muscle state and demonstrate that, similar to normal muscle, myogenic tumors contain functionally distinct cell subsets, including cells lacking myogenic differentiation potential. - Highlights: • Hedgehog activation induces multifocal tumors in skeletal muscle. • These tumors recapitulate skeletal muscle phenotypic and functional heterogeneity. • They contain cells with differential myogenic and adipogenic capacity. • Hedgehog activation enhances satellite cell differentiation.
- OSTI ID:
- 22746397
- Journal Information:
- Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 340; ISSN 0014-4827; ISSN ECREAL
- Country of Publication:
- United States
- Language:
- English
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