A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis

Abstract

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα cells with high CD9 expression (CD9) originates pro-fibrotic cells whereas their CD9 counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRαCD9 fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9 progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.

Properties and functions of adipose tissue macrophages in obesity

“…Using macrophage-specific markers CD64 and MerTK, 38 the population of CD64 À CD11c + ATDCs is identifiable and distinct from CD64 + CD11c + and CD64 + CD11c À ATM pools. CD9 high adipocyte progenitors 41 have been identified as correlating with AT fibrosis in humans, and CD9 is also found on DCs 42 to control antigen presentation, suggesting a potential broader role for CD9 in AT biology that has yet to be understood. 39 Single-cell RNA sequencing and clustering analysis in murine samples suggested that three main ATM populations can be identified by the markers CD9 and Ly6C: 40 Ly6c + ; Ly6c À CD9 + ; and Ly6c À CD9 À .…”

Brown and Beige Adipose Tissues in Health and Disease

“…Diverse beige progenitor lineages may exist; in mice, both beige adipocyte-specific progenitors and beige/white adipocyte-bipotent PDGFRα + progenitors have been reported (60, 178, 338). Notably, a subpopulation of PDGFRα + mesenchymal progenitors (PDGFRα + CD9 high ) also differentiates into fibrogenic cells in obesity, promoting adipose tissue fibrosis (201). …”

“…However, activation of PDGFRα signaling was also reported to stimulate differentiation of adipose mesenchymal progenitors into fibrotic cells at the expense of suppressing adipogenesis (138). Interestingly, a recently study reported an identification of PDGFRα + CD9 high and PDGFRα + CD9 low subsets in adipose tissue (201). The PDGFRα + CD9 high mesenchymal progenitors differentiate into fibrogenic cells, whereas the PDGFRα + CD9 low subset differentiate to adipocytes (201).…”

“…Interestingly, a recently study reported an identification of PDGFRα + CD9 high and PDGFRα + CD9 low subsets in adipose tissue (201). The PDGFRα + CD9 high mesenchymal progenitors differentiate into fibrogenic cells, whereas the PDGFRα + CD9 low subset differentiate to adipocytes (201). Thus, the relative abundance of these two subpopulations is likely to a determinant for the outcome of adipose PDGF signaling.…”

PDGFA regulation of dermal adipocyte stem cells

“…high cells generated fibroblasts whereas CD9 low progenitors were transcriptionally committed to the adipose lineage (18). A more comprehensive understanding of mesenchymal heterogeneity in wounded and unwounded skin will allow researchers to better define the lineage relationships between dermal cells and target specific cellular subsets and signaling pathways that could selectively activate specific "fibroblast" subsets to impact dermal healing and scarring.…”