Lgr5 marks adult progenitor cells contributing to skeletal muscle regeneration and sarcoma formation

• Main Authors: Leung, Carly, Katzrin Bte Ahmad Murad, Tan, Adelyn Liang Thing, Yada, Swathi, Sagiraju, Sowmya, Bode, Peter Karl, Barker, Nick
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2021
• Subjects: Science::Biological sciences; Lgr5; Muscle Regeneration
• Online Access: https://hdl.handle.net/10356/146148
• Institution: Nanyang Technological University

Regeneration of adult skeletal muscle is driven largely by resident satellite cells, a stem cell population increasingly considered to display a high degree of molecular heterogeneity. In this study, we find that Lgr5, a receptor for Rspo and a potent mediator of Wnt/β-catenin signaling, marks a subset of activated satellite cells that contribute to muscle regeneration. Lgr5 is found to be rapidly upregulated in purified myogenic progenitors following acute cardiotoxin-induced injury. In vivo lineage tracing using our Lgr5-2ACreERT2R26tdTomatoLSL reporter mouse model shows that Lgr5+ cells can reconstitute damaged muscle fibers following muscle injury, as well as replenish the quiescent satellite cell pool. Moreover, conditional mutation in Lgr52ACreERT2;KrasG12D;Trp53flox/flox mice drives undifferentiated pleomorphic sarcoma formation in adult mice, thereby substantiating Lgr5+ cells as a cell of origin of sarcomas. Our findings provide the groundwork for developing Rspo/Wnt-signaling-based therapeutics to potentially enhance regenerative outcomes of skeletal muscles in degenerative muscle diseases.