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 3

Tissue atlas: 3-D reconstruction of a fibrogenic niche coregistering mechanics, ECM composition, cell identity, and cell biology.

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Tissue atlas: 3-D reconstruction of a fibrogenic niche coregistering mec...
Shown is a conceptual schematic of a tissue atlas using IPF as an example. Images adapted from Jones et al. (91). A comprehensive tissue atlas would combine — at both the micron and millimeter scale of resolution — static and dynamic mechanical measurements, data regarding ECM composition and organization, cell identity, cell differentiated state, and cell biology (e.g., proliferation markers, signaling footprints). These data would be registered region by region to key morphological features: myofibroblast core and active fibrotic front. With such a data set, investigators would be positioned to generate testable models that pinpoint targetable pathways critical to fibrosis progression based on (a) the precise mechanical properties a cell is sensing, (b) the ECM components a cell is interacting with, and (c) the resulting cell biology as a function of those inputs. Addition of MALDI-imaging mass spectrometry to the picture could provide unprecedented insights into progressive fibrosis (105, 106).