PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity

Tomoaki Iwayama, Cameron Steele, Longbiao Yao, Mikhail G. Dozmorov, Dimitris Karamichos, Jonathan D. Wren, Lorin E. Olson

Research output: Contribution to journalArticle

64 Scopus citations

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 inWAT and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism.

Original languageEnglish
Pages (from-to)1106-1119
Number of pages14
JournalGenes and Development
Volume29
Issue number11
DOIs
StatePublished - 2015

Keywords

  • Adipogenesis
  • Fibrosis
  • Imprinting
  • Nestin
  • Pericyte
  • Platelet-derived growth factor

Fingerprint Dive into the research topics of 'PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity'. Together they form a unique fingerprint.

  • Cite this

    Iwayama, T., Steele, C., Yao, L., Dozmorov, M. G., Karamichos, D., Wren, J. D., & Olson, L. E. (2015). PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes and Development, 29(11), 1106-1119. https://doi.org/10.1101/gad.260554.115