Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle.

A Uezumi,S Fukada,M Nakatani,Y Hamada,H Yamada,N Yamamoto,M Ikemoto-Uezumi,K Tsuchida,M Morita,I Nishino,A Yamaguchi

doi:10.1038/cddis.2014.161

Abstract

Fatty and fibrous connective tissue formation is a hallmark of diseased skeletal muscle and deteriorates muscle function. We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In this study, we report the identification and characterization of a human counterpart to these progenitors. By using PDGFRα as a specific marker, mesenchymal progenitors can be identified in the interstitium and isolated from human skeletal muscle. PDGFRα+ cells represent a cell population distinct from CD56+ myogenic cells, and adipogenic and fibrogenic potentials were highly enriched in the PDGFRα+ population. Activation of PDGFRα stimulates proliferation of PDGFRα+ cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα+ cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. Our results revealed the pathological relevance of PDGFRα+ mesenchymal progenitors to human muscle diseases and provide a basis for developing therapeutic strategy to treat muscle diseases.

Highlights

We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle
CD56 is not expressed by quiescent satellite cells and begins to be expressed only after denervation or differentiation in the mouse,[13,19] both quiescent and activated human satellite cells express CD56, and this molecule has been extensively used as a marker for identification and isolation of satellite cells from human muscle.[20,21,22,23,24,25,26,27,28,29]
M-cadherin,[15] Pax[716–18,32] and CD5620–22,32 have been used as markers for human satellite cell identification, but it was reported that basal lamina staining was necessary for reliable detection of human satellite cells.[18]

Summary

Introduction

We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In response to various regenerative stimuli, satellite cells rapidly become activated and proliferate, and differentiate and fuse with each other or with pre-existing myofibers to regenerate damaged muscle.[1] Satellite cells have been shown to be the major contributor to adult myogenesis,[2,3,4] and several studies have demonstrated that a subset of satellite cells can self-renew in addition to contributing to differentiated progeny, and established their status as adult myogenic stem cells.[5,6,7,8] Despite this exquisite regeneration system, the skeletal muscle is occupied by fatty and fibrous tissue in several pathological conditions such as Duchenne muscular dystrophy (DMD). M-cadherin and Pax[7] are reliable markers for mouse satellite cells[13,14] and were used for human satellite cell identification.[15,16,17,18] CD56 is not expressed by quiescent satellite cells and begins to be expressed only after denervation or differentiation in the mouse,[13,19] both quiescent and activated human satellite cells express CD56, and this molecule has been extensively used as a marker for identification and isolation of satellite cells from human muscle.[20,21,22,23,24,25,26,27,28,29]

Methods

Results

Conclusion