Extracellular matrix as a driver of progressive fibrosis
Jeremy Herrera, … , Craig A. Henke, Peter B. Bitterman
Jeremy Herrera, … , Craig A. Henke, Peter B. Bitterman
Published January 2, 2018
Citation Information: J Clin Invest. 2018;128(1):45-53. https://doi.org/10.1172/JCI93557.
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Review Series

Extracellular matrix as a driver of progressive fibrosis

Abstract

The extracellular matrix (ECM) is dynamically tuned to optimize physiological function. Its major properties, including composition and mechanics, profoundly influence cell biology. Cell-ECM interactions operate through an integrated set of sensor and effector circuits that use several classes of receptors and signal transduction pathways. At the single-cell level, the ECM governs differentiation, metabolism, motility, orientation, proliferation, and survival. At the cell population level, the ECM provides higher-order guidance that is essential for physiological function. When pathological changes in the ECM lead to impairment of organ function, we use the term “fibrosis.” In this Review, we differentiate fibrosis initiation from progression and focus primarily on progressive lung fibrosis impairing organ function. We present a working model to explain how the altered ECM is not only a consequence but also a driver of fibrosis. Additionally, we advance the concept that fibrosis progression occurs in a fibrogenic niche that is composed of a fibrogenic ECM that nurtures fibrogenic mesenchymal progenitor cells and their fibrogenic progeny.

Authors

Jeremy Herrera, Craig A. Henke, Peter B. Bitterman

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Figure 1

ECM-mediated feedback loops during fibrosis initiation and progression.

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ECM-mediated feedback loops during fibrosis initiation and progression. ...
(Upper) Tissue injury leads to TGF-β activation and downstream canonical and noncanonical signals that initiate fibrosis. Once initiated, fibrosis can progress in the absence of the initial stimulus. (Lower) The fibrotic ECM can suppress miR-29, a master negative regulator of stromal genes. This results in increased ribosome recruitment to hundreds of stromal genes and sustained deposition of ECM, thus constituting a positive-feedback loop. Increased matrix stiffness activates the Hippo pathway effector Yes-associated protein 1 (YAP), which can drive ECM deposition and matrix stiffening, constituting another positive-feedback loop. Mesenchymal progenitor cell mechanical memory of substratum stiffness is mediated by miR-21, allowing these progenitors to stably maintain their fibrogenic phenotype and further stiffen the ECM.