Regulation of adipocyte dedifferentiation at the skin wound edge

ABSTRACT Adipocytes have diverse roles in energy storage and metabolism, inflammation, and tissue repair. Mature adipocytes have been assumed to be terminally differentiated cells. However, recent evidence suggests that adipocytes retain substantial phenotypic plasticity, with potential to dedifferentiate into fibroblast-like cells under physiological and pathological conditions. Here, we develop a two-step lineage tracing approach based on the observation that fibroblasts express platelet-derived growth factor receptor alpha ( Pdgfra ) while adipocytes express Adiponectin ( Adipoq ) but not Pdgfra . Our approach specifically traces Pdgfra + cells that originate from Adipoq + adipocytes. We find many traced adipocytes and fibroblast-like cells surrounding skin wounds, but only a few traced cells localize to the wound center. In agreement with adipocyte plasticity, traced adipocytes incorporate EdU, downregulate Plin1 and PPARγ, and upregulate αSMA. We also investigate the role of potential dedifferentiation signals using constitutively active PDGFRα mutation, Pdgfra knockout, or Tgfbr2 knockout models. We find that PDGF and TGFβ signaling both promote dedifferentiation, and PDGFRα does so independently of TGFβR2. These results demonstrate an intersectional genetic approach to trace the hybrid cell phenotype of Pdgfra + adipocytes, which may be important for wound repair, regeneration and fibrosis.