PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity

Abstract

Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRα signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before this transition occurs, PDGFRα signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP+ cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFRα signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism.

Sorting out adipocyte precursors and their role in physiology and disease

“…These data provide direct genetic evidence that perivascular preadipocytes contribute to adipocyte hyperplasia in obesity. This is in line with fate-mapping studies of perivascular nestin + cells in the adipose tissue (NestinCre; Rosa26R tdTomato ), revealing the presence of labeled gonadal adipocytes following high-fat diet (Iwayama et al 2015). It is currently unclear whether the adipogenic capacity of perivascular preadipocytes cells is critical for healthy WAT expansion in the setting of obesity.…”

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.…”

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis

“…Based on previous studies, we knew that PDGFRα activation is sufficient to cause fibrosis in many organs (Olson and Soriano, 2009). We recently found that PDGFRα activation in specific nestin + fibroadipogenic progenitor cells causes WAT fibrosis in adult mice by converting adipogenic progenitor cells into ECM-producing fibroblasts (Iwayama et al, 2015). However, whether PDGFRα activity might influence adipose tissue organogenesis was not explored in previous studies.…”

“…PDGFRα activation also blocks the differentiation of nestin + progenitors into adipocytes in vitro (Iwayama et al, 2015), suggesting that PDGFRα regulates the balance between adipogenic and non-adipogenic mesenchymal cell populations.…”