Lgr5 Marks Adult Progenitor Cells Contributing to Skeletal Muscle Regeneration and Sarcoma Formation

Carly Leung,Carly Leung,Carly Leung,Katzrin Bte Ahmad Murad,Katzrin Bte Ahmad Murad,Katzrin Bte Ahmad Murad,Adelyn Liang Thing Tan,Adelyn Liang Thing Tan,Adelyn Liang Thing Tan,Swathi Yada,Swathi Yada,Swathi Yada,Sowmya Sagiraju,Sowmya Sagiraju,Sowmya Sagiraju,Peter Karl Bode,Nick Barker,Nick Barker,Nick Barker,Nick Barker

doi:10.1016/j.celrep.2020.108535

Abstract

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. Invivo 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.

Highlights

Regeneration of adult skeletal muscle is largely dependent on a quiescent population of muscle satellite cells that is activated in response to injury
We identify a subpopulation of activated satellite cells, which we term muscle progenitor cells (MPCs), that is marked by Lgr5 and contributes to skeletal muscle regeneration in adult mice
We demonstrate that Lgr5+ MPCs contribute to the replenishment of the satellite cell pool and can serve as tumorinitiating cells in the generation of sarcomas

Summary

Introduction

Regeneration of adult skeletal muscle is largely dependent on a quiescent population of muscle satellite cells that is activated in response to injury. The skeletal muscle undergoes a rapid and extensive repair process that is initiated by activation of Pax7+ satellite cells (Lepper et al, 2011; Murphy et al, 2011). These cells generate transit-amplifying myogenic progenitors that undergo expansion and myogenic differentiation, driving the generation and fusion of de novo muscle fibers to existing ones (Zammit et al, 2004). A better understanding of these subpopulations and their biology will undoubtedly enhance our ability to harness progenitor cell subsets for regenerative purposes

Methods

Results

Discussion

Conclusion