Intronic polyadenylation of PDGFRα in resident stem cells attenuates muscle fibrosis

• Published in: Nature (London) 2016-12, Vol.540 (7632), p.276-279
• Main Authors: Mueller, Alisa A., van Velthoven, Cindy T., Fukumoto, Kathryn D., Cheung, Tom H., Rando, Thomas A.
• Format: Article
• Language: English
• Subjects: 631/532/2118/2074; 631/532/489; Adipocytes - cytology; Adipocytes - pathology; Adipogenesis; Animals; Fibroblasts - cytology; Fibroblasts - pathology; Fibrosis - genetics; Fibrosis - pathology; Fibrosis - prevention & control; Humanities and Social Sciences; Introns - genetics; letter; Male; Mice; multidisciplinary; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Diseases - genetics; Muscular Diseases - pathology; Muscular Diseases - prevention & control; Polyadenylation; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptor, Platelet-Derived Growth Factor alpha - chemistry; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Regeneration - genetics; Science; Signal Transduction - genetics; Stem Cells - cytology; Stem Cells - metabolism; Stem Cells - pathology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20160

Changes in intronic polyadenylation of the Pdgfra in fibro/adipogenic progenitors lead to increased expression of a shorter variant with a truncated kinase domain, which modulates pro-fibrotic pathways to reduce tissue fibrosis in muscle. Alternative PDGFRα polyadenylation moderates stem cells Muscle-resident fibrotic and adipogenic progenitors are essential to muscle regeneration but can be detrimental to the repair process if over-activated following prolonged exposure to platelet-derived growth factor (PDGF), leading to the formation of fibrotic tissues. Thomas Rando and colleagues found that these progenitors also induce the production of variants of PDGF receptors, one of which can act as a decoy to inhibit PDGF signalling and prevent the formation of fibrotic tissues. Platelet-derived growth factor receptor α (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signalling through this receptor promotes muscle development in growing embryos and angiogenesis in regenerating adult muscle 1 , 2 . However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis 3 , 4 . This excessive collagen deposition, which is seen in aged and diseased muscle 5 , 6 , 7 , interferes with muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders 8 , 9 . Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show in mice that PDGFRα signalling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated 10 , 11 , 12 , 13 . We found that FAPs produce multiple transcriptional variants of Pdgfra with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signalling and to prevent FAP over-activation. Moreover, increasing the expression of this isoform limits fibrosis in vivo in mice, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem-cell populations.