Editors' ChoicePulmonary fibrosis

Mesenchymal metamorphosis

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Science Translational Medicine  21 Dec 2016:
Vol. 8, Issue 370, pp. 370ec202
DOI: 10.1126/scitranslmed.aal3700

The narrow isthmus of tissue subjacent to the lung alveolus known as the interstitium is home to multiple mesenchymal cell types, including fibroblasts, endothelial cells, pericytes, and smooth muscle cells. These cells play a remarkable role in tissue remodeling during lung fibrosis, but the specific functions of cellular subtypes remain unknown. For example, although a subset of interstitial fibroblasts has been noted to contain lipid droplets leading to their classification as lipofibroblasts, a functional role for lipofibroblasts in disease has yet to be defined.

El Agha et al. tested the hypothesis that interstitial lipofibroblasts give rise to pathogenic myofibroblasts in a mouse model of lung fibrosis consisting of airway instillation of bleomycin. Myofibroblasts are intensely studied in fibrosis because they deposit collagen and other elements of fibrotic scar. A hallmark of myofibroblasts is the expression of Acta2, or alpha smooth muscle actin. The authors first observed that cells lineage labeled for Acta2 expression prior to the induction of fibrosis did not subsequently localize to areas of fibrotic scar. This suggests that a cell type that does not express Acta2 at baseline differentiates into the myofibroblast. Using a novel Adrp reporter mouse to lineage label lipofibroblasts prior to induction of fibrosis, the authors found that a large fraction of Acta2-positive myofibroblasts in fibrotic scar also expressed the lipofibroblast lineage label for Adrp, suggesting a phenotypic switch during fibrosis. Moreover, the authors observed loss of Acta2 expression and rising Ardp expression in the mouse model when following cells that were lineage labeled for Acta2 after bleomycin instillation into the recovery phase, suggesting a reversion from the myofibroblast to the lipofibroblast phenotype during resolution of fibrosis.

The authors then investigated the relevance of these findings in human disease. Lung samples from patients with idiopathic pulmonary fibrosis (IPF) had decreased lipofibroblast marker expression compared with non-IPF control samples. Although these data are cross-sectional and do not demonstrate differentiation of lipofibroblasts into myofibroblasts coincident with onset of clinical IPF, treatment of cultured human lung fibroblasts with the master profibrotic cytokine transforming growth factor–β (TGF-β) suppressed ADRP expression and increased expression of the myofibroblast markers ACTA2 and collagen (COL1A1). Since the transcription factor peroxisome proliferator–activated receptor γ (PPARγ) is a known regulator of lipogenic differentiation, its expression was measured and found to be suppressed by TGF-β. However, concurrent treatment with the PPARγ agonist rosiglitazone blunted TGF-β–induced suppression of ARDP and up-regulation of ACTA2 and COL1A1.

Taken together, these findings reveal a novel functional identity for lipofibroblasts in fibrosis. Furthermore, the in vitro studies demonstrating that PPARγ agonism suppresses lipofibroblast transdifferentiation provide a potential approach to testing whether this process contributes to lung fibrosis and could be targeted for therapy.

E. El Agha et al., Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell 10.1016/j.stem.2016.10.004 (2016). [Abstract]

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