A wound site begins as a void or zone of destruction that must be reorganized by adjacent and circulating cells into a tissue that has both mechanical integrity and proper architecture. This reorganization is determined by the progressive construction and remodeling of an extracellular matrix (ECM) that serves as a scaffold for cell migration and growth. In the absence of a matrix, cells cannot move or carry out their normal duties. The matrix around cells defines a microenvironment that provides both mechanical and biochemical information to cells through specific receptors, and it also acts as a biological buffer for the cell-derived signals that drive wound healing.
The orchestrated process of wound healing is carried out by a characteristic progression of cellular performers that communicate by using hormone-like signal proteins: growth factors and cytokines. Each of these signals is recognized on the target cell surface by specific receptors, which then convert the binding interaction into a chemical signal within the cell. The term cytokines is used to describe a collection of small protein signal molecules that are principally derived from cells of the inflammatory system.1 Perhaps the best-known cytokines are the interleukins,2 leukocyte intercellular signaling molecules; however, a wide variety of other secreted cytokines interact with their receptors to induce responses such as cell movement, cell differentiation, or even cell death. In contrast to cytokines, which are frequently involved in regulating inflammation, the cellular growth factors are a distinct group of proteins crucial to the repair process.3 As implied by their name, the principal function of these protein molecules is to promote cell and tissue growth, although these molecules often stimulate cell movement, migration, and differentiation. Some of the growth factors also affect the processes of extracellular matrix accumulation and remodeling. All these signal molecules are regarded as hormones that act at the local tissue level to bring about specific tissue responses. As such, they act in autocrine, paracrine, or juxtacrine fashion, depending on the nature of the target cell. (Fig. 3.1) Growth factors are also stored and released by the extracellular matrix, and many of the signals generated by these factors will occur only if the cell is also bound to an extracellular matrix. (Fig. 3.2)
Principles of growth factor interaction. Cells both secrete and react to growth factors as a form of intercellular communication. There are three basic modes of signal transmission. Autocrine signaling is a mode in which a cell can drive an internal feedback loop by secreting factors (proteins in the case of growth factors) that are bound to and recognized by receptors on the same cell. Receptor binding then signals to the cell interior. In paracrine signaling, two different cell types communicate, and there is often an extracellular matrix between them. This matrix often contains highly charged, sulfated sugars bound to proteins (heparan sulfate proteoglycans) that can trap the growth factors in ...