The extracellular matrix: an active or passive player in fibrosis?

Abstract

Fibrosis is characterized by excessive accumulation of collagen and other extracellular matrix (ECM) components, and this process has been likened to aberrant wound healing. The early phases of wound healing involve the formation of a provisional ECM containing fibrin, fibrinogen, and fibronectin. Fibroblasts occupy this matrix and proliferate in response to activators elaborated by leukocytes that have migrated into the wound and are retained by the ECM. This coincides with the appearance of the myofibroblast, a specialized form of fibroblast whose differentiation is primarily driven by cytokines, such as transforming growth factor-β (TGF-β), and by mechanical tension. When these signals are reduced, as when TGF-β secretion is reduced, or as in scar shrinkage, myofibroblasts undergo apoptosis, resulting in a collagen-rich, cell-poor scar. Retention of myofibroblasts in fibrosis has been described as the result of imbalanced cytokine signaling, especially with respect to levels of activated TGF-β. ECM components can regulate myofibroblast persistence directly, since this phenotype is dependent on extracellular hyaluronan, tenascin-C, and the fibronectin splice variant containing the "extra domain A," and also, indirectly, through retention of TGF-β-secreting cells such as eosinophils. Thus the ECM is actively involved in both cellular and extracellular events that lead to fibrosis. Targeting components of the ECM as cells respond to injury and inflammatory stimuli holds promise as a means to avoid development of fibrosis and direct the wound-healing process toward reestablishment of a healthy equilibrium.

Figures

Fig. 1.

Influence of extracellular matrix (ECM) on cell behavior. Cells interact with specific components of the ECM. These interactions govern, to a large extent, the ability of cells to adhere to that ECM, proliferate, and migrate, as well as to survive and resist cell death. In turn, the cells remodel and produce new ECM, allowing these events to take place.

Fig. 2.

Transition of healthy tissue to fibrotic tissue. A proposed sequence of events highlighting a stepwise remodeling of the ECM that involves alterations in the composition of the ECM and effects on cell phenotype that eventually result in tissue fibrosis. A central component in this pathway is the temporal generation of the major collagen-secreting cell, the myofibroblast, from resident fibroblasts. As an alternative pathway, circulating cells such as fibrocytes or other stem cells may directly engraft into tissue and transdifferentiate into myofibroblasts, promoting fibrosis. TGF-β, transforming growth factor-β; CTGF, connective tissue growth factor.

Fig. 3.

ECM transitions required for cell proliferation and migration. For cells to change shape so they can divide and/or migrate, they must modify their external environment by first degrading the existing ECM and replacing it with components that allow the cell to change shape and move. Two ECM molecules that are produced during these events and allow this to happen are hyaluronan and versican.

Fig. 4.

ECM and immune cell regulation. Immune cells come into contact with the ECM as they invade tissue as part of the inflammatory phase of tissue repair. Certain types of ECMs, including those that contain hyaluronan (HA) and versican, interact with myeloid and lymphoid cells through specific cell surface receptors to promote their invasion, accumulation, and activation. Such matrices may exhibit either pro- or anti-inflammatory properties. Targeting specific ECM components involved in these interactions may be one strategy to interfere with subsequent events driven by these cells that lead to fibrosis. This figure was prepared by Dr. Charles W. Frevert, University of Washington, Seattle, WA, and is used with permission.