title: 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.
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Iwayama
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
authors.forename: Cameron
authors.initials: C
authors.lastname: Steele
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
authors.forename: Longbiao
authors.initials: L
authors.lastname: Yao
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA; Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia 23298, USA;
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Dozmorov
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA; Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Karamichos
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA; lorin-olson@omrf.org.
authors.forename: Lorin E
authors.initials: LE
authors.lastname: Olson
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000166:cytology* / Q000503:physiopathology*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D017690:Cell Transplantation; D002478:Cells, Cultured; D005355:Fibrosis / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000473:pathology
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: Nestin; adipogenesis; fibrosis; imprinting; pericyte; platelet-derived growth factor