Regulating the Cell Differentiation Trajectory of Progenitor Cells in Adipose Tissue Fibrosis

Adipose fibrosis signifies pathological remodeling of white adipose tissue (WAT) associated with insulin resistance, diabetes, and cardiovascular disease. Matrix Gla protein (MGP) balances bone morphogenic protein (BMP) and transforming growth factors (TGF) β signaling but has an unclear role in WAT. Our study showed that Mgp gene deletion promotes fibrosis and impairs adipogenesis in mice with global or platelet-derived growth factor receptor α (Pdgfrα)-Cre-mediated Mgp deletion in APCs. Single cell RNA sequencing showed two new adipose-derived stem cells (ASC) populations, ASC1 and ASC4, emerging after Mgp deletion. Trajectory analysis found that ASC1 and ASC4 were derived from ASC2, which normally undergo adipogenesis but instead had diverted to fibrogenic differentiation. All three ASCs expressed Pdgfrα and dipeptidyl peptidase 4 (Dpp4). Signaling studies in mice with Pdgfrα-Cre-mediated Mgp deletion using SB431542 or sitagliptin reduced TGFβ activity, the size of the PDGFRα+, DPP4+ cell population and fibrogenesis. Dysregulation of PDGFRα+, DPP4+ cells may signal early adipose fibrosis. Stromal vascular fraction (SVF) cells from inguinal (subcutaneous) white adipose tissue were were isolated from Mgp-KO, wild-type, and pdgfra-cre mediated Mgp deletion mice, followed by enzymatic digestion. After dead and immuno cells were removed by DAPI and Cd45 staining using FACS, live cells were sent for scRNA-sequencing.