Title

Skeletal Muscle Satellite Cells Have a MyoD-Positive Developmental Origin and Activated MyoD-Positive Satellite Cells Maintain Their Self-renewal Capacity during Adult Muscle Regeneration

Date of Completion

January 2011

Keywords

Biology, Molecular|Biology, Genetics|Biology, Cell

Degree

Ph.D.

Abstract

Skeletal muscle satellite cells (SCs) are tissue-specific adult stem cells responsible for muscle growth and regeneration. The lack of specific markers for progenitors of SCs during their early embryonic development made it impossible to determine SCs' developmental origin. Here, we have developed the MyoDiCre knock-in mouse line and used the Cre/lox lineage analysis to determine whether satellite cell progenitors express MyoD, a marker of myogenic commitment. An extensive survey of hind limb, intercostal, diaphragm, and extraocular muscle in adult and neonatal mice showed that almost all SCs were labeled and derived from MyoD-positive committed myogenic progenitors. ^ Previously, the absence of a permanent and specific labeling method of activated adult SC in vivo resulted in controversies regarding the mechanisms of renewal of SCs upon muscle injury. To address this issue, we developed the MyoDCreER knock-in mouse line, a ligand-dependent inducible Cre-expressing mouse, to control the timing of recombination of MyoD-positive cells and investigate whether activated MyoD-positive SC progeny can transition back to become quiescent SCs in the regenerated muscle. Using this method, recombined SCs were found to reoccupy the SC niche after regeneration is complete, which revealed a possible mechanism for SC repopulations and maintenance by self-renewal in spite of MyoD expression. Furthermore, with stage-specific induction, we demonstrated that self-renewal occurs within two days after injury, suggesting a rapid down regulation of MyoD expression to prevent terminal myogenic differentiation due to MyoD expression. ^ In conclusion, these findings bring new insight to the role of MyoD. We demonstrated that transient MyoD expression during embryonic development commits SC precursors to the myogenic fate. We also showed that transient MyoD expression in activated SCs does not necessarily result in terminal differentiation, but can be reversed or suppressed, and activated MyoD-positive SCs can self-renewal. ^