PDGF receptor signal mediates the contribution of Nestin-positive cell lineage to subcutaneous fat development

The beiging of white adipose tissue (WAT) is expected to improve systemic metabolic conditions; however, the regulation and developmental origin of this process remain insufficiently understood. In the present study, the implication of platelet-derived growth factor receptor alpha (PDGFRα) was examined in the beiging of inguinal WAT (ingWAT) of neonatal mice. Using in vivo Nestin expressing cell (Nestin⁺) lineage tracing and deletion mouse models, we found that, in the mice with Pdgfra gene inactivation in Nestin⁺ lineage (N-PRα-KO mice), the growth of inguinal WAT (ingWAT) was suppressed during neonatal periods as compared with control wild-type mice. In the ingWAT of N-PRα-KO mice, the beige adipocytes appeared earlier that were accompanied by the increased expressions of both adipogenic and beiging markers compared to control wild-type mice. In the perivascular adipocyte progenitor cell (APC) niche of ingWAT, many PDGFRα⁺ cells of Nestin⁺ lineage were recruited in Pdgfra-preserving control mice, but were largely decreased in N-PRα-KO mice. This PDGFRα⁺ cell depletion was replenished by PDGFRα⁺ cells of non-Nestin⁺ lineage, unexpectedly resulting in an increase of total PDGFRα⁺ cell number in APC niche of N-PRα-KO mice over that of control mice. These represented a potent homeostatic control of PDGFRα⁺ cells between Nestin⁺ and non-Nestin⁺ lineages that was accompanied by the active adipogenesis and beiging as well as small WAT depot. This highly plastic nature of PDGFRα⁺ cells in APC niche may contribute to the WAT remodeling for the therapeutic purpose against metabolic diseases.