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Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

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  • Brendan Evano
  • Diljeet Gill
  • Irene Hernando-Herraez
  • Glenda Comai
  • Thomas M Stubbs
  • Pierre-Henri Commere
  • Wolf Reik
  • Shahragim Tajbakhsh

Abstract

Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.Author summary: Adult skeletal muscles are regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in expression of key myogenic regulators and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct transcriptome and DNA methylation signatures, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs adopted host-site specific positional Hox codes after engraftment within the host muscle. However, about 10% of EOM-specific genes were resistant to alterations following heterotopic engraftment, pointing to molecular determinants of the high engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.

Suggested Citation

  • Brendan Evano & Diljeet Gill & Irene Hernando-Herraez & Glenda Comai & Thomas M Stubbs & Pierre-Henri Commere & Wolf Reik & Shahragim Tajbakhsh, 2020. "Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation," PLOS Genetics, Public Library of Science, vol. 16(10), pages 1-21, October.
  • Handle: RePEc:plo:pgen00:1009022
    DOI: 10.1371/journal.pgen.1009022
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    2. Irene Hernando-Herraez & Brendan Evano & Thomas Stubbs & Pierre-Henri Commere & Marc Bonder & Stephen Clark & Simon Andrews & Shahragim Tajbakhsh & Wolf Reik, 2019. "Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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    1. Felicia Lazure & Rick Farouni & Korin Sahinyan & Darren M. Blackburn & Aldo Hernández-Corchado & Gabrielle Perron & Tianyuan Lu & Adrien Osakwe & Jiannis Ragoussis & Colin Crist & Theodore J. Perkins , 2023. "Transcriptional reprogramming of skeletal muscle stem cells by the niche environment," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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