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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 7

TGF-β1 induced mechanotransduction pathway of α-SMA+ pericyte (PC) accumulation in pulmonary fibrosis.

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TGF-β1 induced mechanotransduction pathway of α-SMA+ pericyte (PC) accum...
(A) Pericyte abundant microvasculature reside in the human lung. (B) Production of TGF-β1 by fibroblasts and resident macrophages in the interstitial space results in accumulation of α-SMA+ PC in the fibrotic foci. (C) [1] The binding of TGF-β1 to TGF-βR1 and TGF-βR2 on the surface of PC initiates a Smad signaling cascade. [2] Smad2/3 gets phosphorylated and [3] translocates to the cell’s nucleus. [4] The accumulation of P-Smad2/3 in the nucleus leads to increased binding to the Smad binding element (SBE), which results in increased transcription of fibrotic genes. [5] Increased production of matrix proteins, including collagen I, results in an increased ECM stiffness. [6] Focal adhesion and focal adhesion kinases (FAK) binding to the stiffened environment results in [7] increased translocation of megakaryoblastic leukemia 1 (MKL-1), yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), resulting in [8] increased α-SMA expression and myofibroblast transition.

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