Muscle-resident PDGFRβ+ cells, which include pericytes and PW1 + interstitial cells (PICs), play a dual role in muscular dystrophy. They can either undergo myogenesis to promote muscle regeneration or differentiate into adipocytes and other cells to compromise regeneration. How the differentiation and fate determination of PDGFRβ+ cells are regulated, however, remains unclear. Here, by utilizing a conditional knockout mouse line, we report that PDGFRβ+ cell-derived laminin inhibits their proliferation and adipogenesis, but is indispensable for their myogenesis. In addition, we show that laminin alone is able to partially reverse the muscle dystrophic phenotype in these mice at the molecular, structural and functional levels. Further RNAseq analysis reveals that laminin regulates PDGFRβ+ cell differentiation/fate determination via gpihbp1. These data support a critical role of laminin in the regulation of PDGFRβ+ cell stemness, identify an innovative target for future drug development and may provide an effective treatment for muscular dystrophy.
Bibliographical noteFunding Information:
We thank Dr Volkhard Lindner (Maine Medical Center Research Institute) for the Pdgfrb-Cre+ mice and Dr So-ichiro Fukada (Osaka University) for the SM/C-2.6 antibody. We thank the Electron Microscopy Center and Flow Cytometry Center for technical support and assistance. We also thank Dr Christer Betsholtz for valuable scientific discussion and suggestions. This work was supported by NIH grant NS050537 (S.S.), Myotonic Dystrophy Foundation Fund-A-Fellow Grant (Y.Y.), Merck Postdoctoral Fellowship (Y.Y.) and BD Stem Cell Grant (Y.Y.). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.