Muscle Stem Cells Undergo Extensive Clonal Drift during Tissue Growth via Meox1-Mediated Induction of G2 Cell-Cycle Arrest

Publication date: 6 July 2017
Source:Cell Stem Cell, Volume 21, Issue 1
Author(s): Phong Dang Nguyen, David Baruch Gurevich, Carmen Sonntag, Lucy Hersey, Sara Alaei, Hieu Tri Nim, Ashley Siegel, Thomas Edward Hall, Fernando Jaime Rossello, Sarah Elizabeth Boyd, Jose Maria Polo, Peter David Currie
Organ growth requires a careful balance between stem cell self-renewal and lineage commitment to ensure proper tissue expansion. The cellular and molecular mechanisms that mediate this balance are unresolved in most organs, including skeletal muscle. Here we identify a long-lived stem cell pool that mediates growth of the zebrafish myotome. This population exhibits extensive clonal drift, shifting from random deployment of stem cells during development to reliance on a small number of dominant clones to fuel the vast majority of muscle growth. This clonal drift requires Meox1, a homeobox protein that directly inhibits the cell-cycle checkpoint gene ccnb1. Meox1 initiates G2 cell-cycle arrest within muscle stem cells, and disrupting this G2 arrest causes premature lineage commitment and the resulting defects in muscle growth. These findings reveal that distinct regulatory mechanisms orchestrate stem cell dynamics during organ growth, beyond the G0/G1 cell-cycle inhibition traditionally associated with maintaining tissue-resident stem cells.

Graphical abstract

Teaser

Currie and colleagues reveal a dramatic clonal drift of muscle stem cells during tissue growth, which is regulated at the G2 phase of the cell cycle via Meox1-dependent control of ccnb1. This contrasts with G0/G1 phase control evident in adult stem cells, indicating divergent modes of stem cell regulation.


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