In healthy tissue, the ECM provides an optimal environment for normal cell functions. Thus the composition of the ECM is in a constant state of flux during development and disease. In turn, the cells remodel the ECM, allowing these events to take place ( Fig. The ECM interacts with cells to influence adhesion, proliferation, migration, and survival ( 27). 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. Thus the ECM is actively involved in both cellular and extracellular events that lead to fibrosis. 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. Retention of myofibroblasts in fibrosis has been described as the result of imbalanced cytokine signaling, especially with respect to levels of activated TGF-β. 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. ![]() 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. ![]() 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. The early phases of wound healing involve the formation of a provisional ECM containing fibrin, fibrinogen, and fibronectin. Fibrosis is characterized by excessive accumulation of collagen and other extracellular matrix (ECM) components, and this process has been likened to aberrant wound healing.
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