Fibrosis and Adipogenesis

Fibrosis is a disease process where excessive deposition of collagen-rich extracellular matrix leads to organ dysfunction. Proliferating fibroblasts and their contractile derivatives, called myofibroblasts, are the main cell types in fibrosis. Adipogenesis is the process of a fibroblast differentiating into a fat cell (adipocyte), which does not cause fibrosis. Organ fibrosis is often accompanied by the disappearance of adipocytes and replacement by myofibroblasts, suggestive of a cell fate switch. As an example, scleroderma is a deadly autoimmune disease where the fatty layer of the skin is replaced by fibrotic scar tissue (Iwayama 2013). Fibroblasts are multipotent and can differentiate into myofibroblasts or adipocytes. On the other hand, in pathological contexts, myofibroblasts and adipocytes can reverse their phenotype and become fibroblasts once again. We are investigating the signals and transcription factors that regulate cell fate decisions in the tripartite fibroblast-myofibroblast-adipocyte (FMA) lineage.

PDGF receptors are expressed in the FMA lineage but they are not expressed on mature adipocytes. Our investigations of the function of PDGFRs have shown that elevated PDGFRα signaling causes severe progressive fibrosis in the skin, fat, intestine, and muscle, with lesser fibrotic accumulations in the lung, kidney and heart (Olson & Soriano 2009). This fibrosis arises, at least in part, from perivascular fibroblasts around large blood vessels (Iwayama 2015). During development and in adult mice, elevated PDGFRα signaling inhibits fibroblasts from differentiating into adipocytes or myofibroblasts (Sun 2017, Sun 2020, Yao 2022). Differentiation-resistant PDGFRα-activated fibroblasts continually proliferate and secrete collagen, thus accounting for severe fibrosis that replaces adipocytes and does not involve myofibroblasts. Conversely, the loss of PDGFRα or PDGFRβ facilitates fibroblast differentiation into adipocytes (Sun 2020). These results imply that downregulation of PDGF signaling in fibroblastic progenitors is a critical step for myofibroblast and adipocyte differentiation.