Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle

Abstract

Muscle stem cells (satellite cells) are distributed throughout the body and have heterogeneous properties among muscles. However, functional topographical genes in satellite cells of adult muscle remain unidentified. Here, we show that expression of Homeobox-A (Hox-A) cluster genes accompanied with DNA hypermethylation of the Hox-A locus was robustly maintained in both somite-derived muscles and their associated satellite cells in adult mice, which recapitulates their embryonic origin. Somite-derived satellite cells were clearly separated from cells derived from cranial mesoderm in Hoxa10 expression. Hoxa10 inactivation led to genomic instability and mitotic catastrophe in somite-derived satellite cells in mice and human. Satellite cell–specific Hoxa10 ablation in mice resulted in a decline in the regenerative ability of somite-derived muscles, which were unobserved in cranial mesoderm–derived muscles. Thus, our results show that Hox gene expression profiles instill the embryonic history in satellite cells as positional memory, potentially modulating region-specific pathophysiology in adult muscles.

Key concepts in muscle regeneration: muscle “cellular ecology” integrates a gestalt of cellular cross-talk, motility, and activity to remodel structure and restore function

“…Recently Hox10 expression and epigenetic methylation events at the Hox-A locus were found to mediate the topographical distribution of differential responsiveness by adult muscle stem cells (Yoshioka et al 2021 ). This paper recalled earlier reports on cranial muscles that present continuous “remodeling” through satellite cell turnover and fusion into undamaged muscle fibers above levels seen in limb muscle fibers (e.g., McLoon and Wirtschafter 2002 , 2003 ; McLoon et al 2004 ).…”

A transcriptome atlas of leg muscles from healthy human volunteers reveals molecular and cellular signatures associated with muscle location

“…Here, we show that both HOXA and HOXC gene family are expressed in myofibers, and their expression levels differs between leg muscles. Yoshioka, Nagahisa et al (2021) also showed expression of HOX genes in adult human muscle tissues. Yet, Terry, Zhang et al (2018) concluded that the expression pattern of Hox genes in adult muscles is insufficient to explain the mRNA expression diversity in adult mouse skeletal muscles.…”

Hox Proteins in the Regulation of Muscle Development

“…Recently, much attention has been given to the role of Hox proteins in adult muscle stem cells (MuSCs), also known as satellite cells, able to regenerate adult muscles upon injury ( Machado et al, 2017 ; Evano et al, 2020 ; Yoshioka et al, 2021 ). It is now accepted that depending on the anatomical position of the muscle, satellite cells display heterogeneity in their proliferative and regenerative properties ( Ono et al, 2010 ).…”

“…It is now accepted that depending on the anatomical position of the muscle, satellite cells display heterogeneity in their proliferative and regenerative properties ( Ono et al, 2010 ). Searching for underlying molecular determinants, Hox-A and Hox-C clusters were found to have different methylation profiles and thus be differentially expressed in adult muscles and their satellite cells derived from somites, compared to the ones derived from the cranial mesoderm ( Evano et al, 2020 ; Yoshioka et al, 2021 ). Knowing that the cranial-derived, Hox-free, satellite cells display higher regenerative capacity than the limb, Hox-expressing satellite cells, an appealing possibility is that Hox could be involved in this process ( Evano et al, 2020 ).…”

“…Interestingly, Hoxa9 deletion in satellite cells from aged adult mice was sufficient to improve their regenerative capacity, suggesting that Hox expression in these cells would have a negative effect on muscle regeneration. A conditional depletion of Hoxa10 leads to a repair default of some somite, but not cranio-derived muscles, explained by a genomic instability and consequent proliferation arrest of adult satellite cells ( Yoshioka et al, 2021 ). Different Hox would thus assume opposed functions in satellite cell proliferation and could account for different capacities of distinct muscle groups to regenerate, a hypothesis that needs to be investigated further.…”