Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis
Fibrosis occurs in skeletal muscle under various pathophysiological conditions such as Duchenne muscular dystrophy (DMD), a devastating disease characterized by fiber degeneration that results in progressive loss of muscle mass, weakness and increased extracellular matrix (ECM) accumulation. Fibrosis is also observed after skeletal muscle denervation and repeated cycles of damage followed by regeneration. The ECM is synthesized largely by fibroblasts in the muscle connective tissue under normal conditions. Myofibroblasts, cells that express α-smooth muscle actin (α-SMA), play a role in many tissues affected by fibrosis. In skeletal muscle, fibro/adipogenic progenitors (FAPs) that express cell-surface platelet-derived growth factor receptor-α (PDGFR-α) and the transcription factor Tcf4 seem to be responsible for connective tissue synthesis and are good candidates for the origin of myofibroblasts. We show that cells positive for Tcf4 and PDGFR-α are expressed in skeletal muscle under normal conditions and are increased in various skeletal muscles of mdx mice, a murine model for DMD, wild type muscle after sciatic denervation and muscle subjected to chronic damage. These cells co-label with the myofibroblast marker α-SMA in dystrophic muscle but not in normal tissue. The Tcf4-positive cells lie near macrophages mainly concentrated in dystrophic necrotic-regenerating foci. The close proximity of Tcf4-positive cells to inflammatory cells and their previously described role in muscle regeneration might reflect an active interaction between these cell types and growth factors, possibly resulting in a muscular regenerative or fibrotic condition.
KeywordsTcf4 PDGFR-α Fibroblasts Muscular dystrophy Fibrosis
α-Smooth muscle actin
Duchenne muscular dystrophy
Platelet-derived growth factor receptor-α
Transforming growth factor-β
Tumor necrosis factor type α
The authors are grateful to Darling Vera, Lina Correa, Victor Troncoso and Ana Vasquez for their technical support and to Ximena Verges for help with the confocal microscopy.
O.C. conducted most of the experiments. O.C. and E.B. conceived the concepts, designed the study, analyzed the data and wrote the manuscript. D.R. and J.E.O. contributed to the denervation and chronic damage studies, respectively. H.O. helped with the Pax7 and NG2 cell type analyses. All authors read and approved the final version of the manuscript.
Compliance with ethical standards
The authors declare no competing financial interests.
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