Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

• DOI: 10.1016/j.cmet.2021.10.001
• Publication Date: 2021-10-22T05:52:52Z
• Authors: Jean Farup; Jesper Just; Frank de Paoli; Lin Lin; Jonas Brorson Jensen; Tine Billeskov; Ines Sanchez Roman; Cagla Cömert; Andreas Buch Møller; Luca Madaro; Elena Groppa; Rikard Göran Fred; Ulla Kampmann; Lars C. Gormsen; Steen B. Pedersen; Peter Bross; Tinna Stevnsner; Nikolaj Eldrup; Tune H. Pers; Fabio M.V. Rossi; Pier Lorenzo Puri; Niels Jessen
• Keywords: 0301 basic medicine; Skeletal muscle; Fatty degeneration; fibroblast; ACTIVATION; Adipocytes; Metabolismo; INSULIN-RESISTANCE; Biología molecular; Adipogenesis; Type 2 diabetes; Cell Differentiation; Extracellular matrix; 3. Good health; FIBRO/ADIPOGENIC PROGENITORS; Muscular Atrophy; Diabetes mellitus tipo 2; Fibroblast; type 2 diabetes; fibro-adipogenic progenitors; STEM-CELLS; Enfermedad; Fibro-adipogenic progenitors; 616.379-008.64; 572; adipocytes; extracellular matrix; 610; 2411 Fisiología Humana; METABOLISM; Fisiología; 03 medical and health sciences; STAIN-FREE TECHNOLOGY; POLYADENYLATION; Muscular Diseases; 3207 Patología; Humans; PDGFR-ALPHA; skeletal muscle; Muscle, Skeletal; DECREASES; mesenchymal stem cells; fibrosis; Biología molecular (Biología); adipocytes; extracellular matrix; fatty degeneration; fibro-adipogenic progenitors; fibroblast; fibrosis; mesenchymal stem cells; skeletal muscle; type 2 diabetes; fatty degeneration; Fibrosis; Diabetes Mellitus, Type 2; Mesenchymal stem cells; RESIDENT

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.