Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis

Abstract

Summary Tissue growth and maintenance requires stem cell populations that self-renew, proliferate and differentiate. Maintenance of white adipose tissue (WAT) requires the proliferation and differentiation of adipocyte stem cells (ASCs) to form postmitotic, lipid-filled mature adipocytes. Here, we use the dynamic adipogenic program that occurs during hair growth to uncover an unrecognized regulator of ASC self-renewal and proliferation, Pdgfa, which activates Akt signaling to drive and maintain the adipogenic program in the skin. Pdgfa expression is reduced in aged ASCs and is required for ASC proliferation and maintenance in the dermis but not in other WATs. Our molecular and genetic studies uncover PI3K/Akt2 as a direct Pdgfa target, activated in ASCs during WAT hyperplasia and functionally required for dermal ASC proliferation. Our data therefore reveal active mechanisms that regulate ASC self-renewal in the skin and show that distinct regulatory mechanisms operate in different WAT depots.

PDGFA regulation of dermal adipocyte stem cells

“…The authors discuss two observed effects from the stimulation of PDGFR in adipose progenitors. Our study showed that decreased PDGFRα signaling leads to a loss of ASCs (8), while a prior study showed that an expression of a constitutively active PDGFRα mutant in mesenchymal cells leads to fibrosis (19,20). It is possible that the level of receptor activation might determine whether the biological response will be maintenance of ASCs or induction of fibrosis.…”

“…The expansion of dWAT during hair growth occurs through activation of adipocyte precursors that have been identified in other tissues as adipocyte stem cells (ASCs) and enlargement of existing mature adipocytes (6,7). Recent work from our group revealed a role for PDGF signaling in maintaining a sub-population of ASCs (8). Some of these findings have been recently discussed by two editorials from Cappellano & Ploner (9) and Dani & Pfeifer (10).…”

“…Our research revealed that PDGF signaling is important for maintaining dWAT ASCs. We also examined the numbers of ASCs from perigonadal and inguinal white adipose tissue in Pdgfa cKO mice and failed to observe changes in ASC numbers (8).…”

“…Another explanation could be the accelerated rate of adipocyte generation displayed by skin. Skin generates new adipocytes during the transition from the quiescent phase (telogen) to the growth phase (anagen) of the hair follicle cycle in as little as 2 weeks (6,8 (14). The rapid transition from precursor to adipocyte in the skin suggests that either dWAT precursors or environmental factors differ dramatically from other adipose depots or that while regulation might be similar between different depots, the time frame in which biological processes happen greatly differ between individual depots.…”

Sorting out adipocyte precursors and their role in physiology and disease

“…In adulthood, adipocyte turnover occurs at a rate of ∼10% per year (Spalding et al 2008). In rodents, the degree of turnover may be higher, varying from depot to depot (Wang et al 2013;Rivera-Gonzalez et al 2016). A remarkable and unique property of adipose tissue is the tremendous capacity to expand or contract in different physiological settings.…”