Editors' ChoiceFibrosis

On the origin of fat fibrosis

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Science Translational Medicine  10 Jun 2015:
Vol. 7, Issue 291, pp. 291ec98
DOI: 10.1126/scitranslmed.aac5098

Fibrotic tissue is less functional than its healthy counterparts. When white adipose tissue (WAT) undergoes fibrosis, which can occur in obesity, it is associated with metabolic dysfunction and insulin resistance. But what causes this inappropriate tissue transformation and excessive extracellular matrix buildup in WAT? Now, Iwayama et al. reveal the origin of the cells undergoing this pathological transformation, as well as the molecular trigger.

Mice were engineered to express a mutant, constitutively active version of the platelet-derived growth factor receptor alpha (PDGFRα) specifically in perivascular cells (pericytes or pericyte-like cells and adventitial cells in the outermost layer of large blood vessels). In WAT, this special cell population is newly recognized as adipocyte precursors; but turning on PDGFRα signaling (a pathway established to trigger fibrosis in other organs) is sufficient to override their predisposition toward adipogenesis (fat formation), causing these cells to become profibrotic in mice. By tracking perivascular cells over time, Iwayama et al. observed that PDGFRα signaling caused them to expand, secrete extracellular matrix, and thus constitute substantial fibrosis in subcutaneous fat, as well as in other tissue types, such as intestinal submucosa and skeletal muscle. Remarkably, this fibrotic transformation occurred “naturally,” in the absence of tissue damage or other initiators of inflammation. The authors went on to characterize gene expression and signaling in this multipotent cell population, linking PDGFRα to mRNA translation, as well as epigenetic and, in turn, expression changes in imprinted genes that control cell “stemness.”

The identification of perivascular cells as a source of fibrotic tissue in WAT raises the question whether the relative contribution of different profibrotic cell types to this and other challenging inflammation-associated fibrotic diseases might influence their clinical features, as well as their responsiveness to therapeutics targeting the switch of distinct progenitors.

T. Iwayama et al., PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev. 10.1101/gad.260554.115 (2015). [Abstract]

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