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.

Figure 1. 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.

Figure 2. Polarity of the IPF Fibroblastic Focus.

(A) The fibroblastic focus in IPF is polarized. It contains an active fibrotic front, which is a highly cellular region composed of proliferating fibrogenic MPCs, and activated macrophages embedded in a hyaluronan-rich ECM. The myofibroblast core contains noncycling myofibroblasts actively synthesizing collagen embedded in an ECM rich in collagen I/III/VI, fibronectin, fibrin, fascin, tenascin C, hyaluronan, and latent TGF-β. (B) An example of what is likely a newly developing fibroblastic focus (boxed region) at the advancing fibrotic front at the interface between fibrotic lung on the left and relatively uninvolved lung on the right. (C) Higher-power image of the boxed region in panel B showing the myofibroblast core and the active fibrotic front. At the periphery of the focus, thickened alveolar walls are juxtaposed between the active fibrotic front and morphologically preserved thin alveolar structures (indicated by arrows). This appearance supports a model of fibrosis progression in which cells in the active fibrotic front invade into contiguous morphologically preserved alveolar structures, causing progressive fibrotic destruction of the gas-exchange surface. The mesenchymal cells behind the fibrotic front (the progeny of IPF MPCs) differentiate into myofibroblasts that constitute the fibrotic core. Images adapted from Xia et al. (9).

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

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).