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Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung
Parid Sava, … , Erica L. Herzog, Anjelica L. Gonzalez
Parid Sava, … , Erica L. Herzog, Anjelica L. Gonzalez
Published December 21, 2017
Citation Information: JCI Insight. 2017;2(24):e96352. https://doi.org/10.1172/jci.insight.96352.
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Research Article Cell biology Vascular biology

Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown etiology characterized by a compositionally and mechanically altered extracellular matrix. Poor understanding of the origin of α-smooth muscle actin (α-SMA) expressing myofibroblasts has hindered curative therapies. Though proposed as a source of myofibroblasts in mammalian tissues, identification of microvascular pericytes (PC) as contributors to α-SMA–expressing populations in human IPF and the mechanisms driving this accumulation remain unexplored. Here, we demonstrate enhanced detection of α-SMA+ cells coexpressing the PC marker neural/glial antigen 2 in the human IPF lung. Isolated human PC cultured on decellularized IPF lung matrices adopt expression of α-SMA, demonstrating that these cells undergo phenotypic transition in response to direct contact with the extracellular matrix (ECM) of the fibrotic human lung. Using potentially novel human lung–conjugated hydrogels with tunable mechanical properties, we decoupled PC responses to matrix composition and stiffness to show that α-SMA+ PC accumulate in a mechanosensitive manner independent of matrix composition. PC activated with TGF-β1 remodel the normal lung matrix, increasing tissue stiffness to facilitate the emergence of α-SMA+ PC via MKL-1/MTRFA mechanotranduction. Nintedanib, a tyrosine-kinase inhibitor approved for IPF treatment, restores the elastic modulus of fibrotic lung matrices to reverse the α-SMA+ phenotype. This work furthers our understanding of the role that microvascular PC play in the evolution of IPF, describes the creation of an ex vivo platform that advances the study of fibrosis, and presents a potentially novel mode of action for a commonly used antifibrotic therapy that has great relevance for human disease.

Authors

Parid Sava, Anand Ramanathan, Amelia Dobronyi, Xueyan Peng, Huanxing Sun, Adrian Ledesma-Mendoza, Erica L. Herzog, Anjelica L. Gonzalez

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Figure 4

TGF-β1 promotes extracellular matrix (ECM) remodeling and fibrotic foci formation.

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TGF-β1 promotes extracellular matrix (ECM) remodeling and fibrotic foci ...
(A) PC were cultured on matrices and activated with TGF-β1 for 14 days. Immunofluorescence images of α-SMA (green), vimentin (red), and nuclei (blue) are shown and mean expression ± SEM. (B) α-SMA and vimentin were quantified using flow cytometry (one-way ANOVA with Tukey Post-Hoc test, *P < 0.05 compared with low-stiffness hydrogel of the same activation, #P < 0.05 compared with nonactivated condition of the same hydrogel stiffness, n = 3). (C) Immunofluorescence images of collagen IV (green) and fibronectin (red), or collagen I (green) and laminin (red), of fibrotic lesions are shown, and (D) the mean spatial density ± SEM and (E) mean area ± SEM of the lesions were quantified (one-way ANOVA with Tukey Post-Hoc test, *P < 0.05 versus nonactivated PC, n = 6). (F) Immunofluorescence images of α-SMA and vimentin. (G) α-SMA and (H) vimentin expression quantified using flow cytometry (mean fold increase over nonactivated α-SMA or vimentin ± SEM shown) and (I) confirmed using immunoblotting (Student t test with Bonferroni post-test. *P < 0.05 versus nonactivated PC, n ≥ 10).

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