Odd skipped-related 1 identifies a population of embryonic fibro-adipogenic progenitors regulating myogenesis during limb development

Pedro Vallecillo-García,Sophie Vom Hofe-Schneider,Bernd Timmermann,Giovanna Marazzi,Stefan T Börno,Shinichiro Hayashi,Mickael Orgeur,Frédéric Relaix,Daniel M Ibrahim,Jürgen Stumm,Manuel Koch,Delphine Duprez,Katrin Hildebrandt,Gerhard Sengle,Sigmar Stricker,Verena Kappert,David A Sassoon

doi:10.1038/s41467-017-01120-3

Abstract

Fibro-adipogenic progenitors (FAPs) are an interstitial cell population in adult skeletal muscle that support muscle regeneration. During development, interstitial muscle connective tissue (MCT) cells support proper muscle patterning, however the underlying molecular mechanisms are not well understood and it remains unclear whether adult FAPs and embryonic MCT cells share a common lineage. We show here that mouse embryonic limb MCT cells expressing the transcription factor Osr1, differentiate into fibrogenic and adipogenic cells in vivo and in vitro defining an embryonic FAP-like population. Genetic lineage tracing shows that developmental Osr1+ cells give rise to a subset of adult FAPs. Loss of Osr1 function leads to a reduction of myogenic progenitor proliferation and survival resulting in limb muscle patterning defects. Transcriptome and functional analyses reveal that Osr1+ cells provide a critical pro-myogenic niche via the production of MCT specific extracellular matrix components and secreted signaling factors.

Highlights

Fibro-adipogenic progenitors (FAPs) are an interstitial cell population in adult skeletal muscle that support muscle regeneration
In this study we show that the transcription factor Odd skipped-related 1 (Osr1) marks a subset of embryonic muscle connective tissue (MCT) cells that constitute a developmental FAP-like population, which supports embryonic myogenesis and is a developmental source of adult muscle interstitial FAPs
We show here that Osr1+ cells define a population of embryonic FAPs as a subpopulation of MCT

Summary

Introduction

Fibro-adipogenic progenitors (FAPs) are an interstitial cell population in adult skeletal muscle that support muscle regeneration. There is long-standing evidence that limb muscle patterning is mediated by extrinsic signals from local lateral plate mesoderm derived cells[8,9,10] This non-cell autonomous function is most likely mediated by MCT cells providing local but still undefined cues for myogenic cell proliferation, differentiation, survival and local migration[11,12,13]. In this study we show that the transcription factor Odd skipped-related 1 (Osr1) marks a subset of embryonic MCT cells that constitute a developmental FAP-like population, which supports embryonic myogenesis and is a developmental source of adult muscle interstitial FAPs. We further show that loss of Osr[1] function during limb development leads to a marked decrease in myogenic progenitor expansion and muscle patterning defects. Consistent with these observations, we show that Osr[1] lies upstream of a large number of genes that control muscle connective tissue function

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Conclusion