Porth's Essentials of Pathophysiology, 4e

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Cell Proliferation and Tissue Regeneration and Repair

C h a p t e r 4

There is continued interest in developing growth factors as a means of increasing cell proliferation and enhanc- ing wound healing as well as developing strategies to block growth factor signaling pathways that could be used to inhibit malignant cell proliferation in cancer. Extracellular Matrix and Cell–Matrix Interactions The understanding of tissue regeneration and repair has expanded over the past several decades to encompass the complex environment of the ECM. There are two basic forms of ECM: (1) the basement membrane, which sur- rounds epithelial, endothelial, and smooth muscle cells; and (2) the interstitial matrix, which is present in the spaces between cells in connective tissue and between the epithelium and supporting cells of blood vessels. The ECM is secreted locally and assembles into a net- work of spaces surrounding tissue cells (see Chapter 1). There are three basic components of the ECM: fibrous structural proteins (e.g., collagen and elastin fibers), water-hydrated gels (e.g., proteoglycans and hyaluronic acid) that permit resilience and lubrication, and adhe- sive glycoproteins (e.g., fibronectin, laminin) that con- nect the matrix elements to one another and to cells 1–3,9 (Fig. 4-3). Integrins are a family of transmembrane gly- coproteins that are the main cellular receptors for ECM components such as fibronectin and laminin. They bind to many ECM components, initiating signaling cas- cades that affect cell proliferation and differentiation. Fibroblasts, which reside in close proximity to collagen fibers, are responsible for the synthesis of collagen, elas- tic, and reticular fibers, and complex carbohydrates in the ground substance. The ECM provides turgor to soft tissue and rigidity to bone; it supplies the substratum for cell adhesion; it

is involved in the regulation of growth, movement, and differentiation of the cells surrounding it; and it provides for the storage and presentation of regulatory molecules that control the repair process. The ECM also provides the scaffolding for tissue renewal. Although the cells in many tissues are capable of regeneration, injury does not always result in restoration of normal structure unless the ECM is intact. The integrity of the underly- ing basement membrane, in particular, is critical to the regeneration of tissue. When the basement membrane is disrupted, cells proliferate in a haphazard way, resulting in disorganized and nonfunctional tissues. Critical to the process of wound healing are transi- tions in the composition of the ECM. In the transitional process, the ECM components are degraded by prote- ases (enzymes) that are secreted locally by a variety of cells (fibroblasts, macrophages, neutrophils, synovial cells, and epithelial cells). Some of the proteases, such as the collagenases, are highly specific, cleaving particu- lar proteins at a small number of sites. 10,11 This allows for the structural integrity of the ECM to be retained while healing occurs. Because of their potential to pro- duce havoc in tissues, the actions of the proteases are tightly controlled. They are typically produced in an inactive form that must first be activated by certain chemicals likely to be present at the site of injury, and they are rapidly inactivated by tissue inhibitors. Recent research has focused on the unregulated action of the proteases in disorders such as cartilage matrix break- down in arthritis and neuroinflammation in multiple sclerosis. 11 ■■ The process of tissue growth and repair involves proliferation of functioning parenchymal cells of an organ or body part and its supporting connective tissues and extracellular matrix. ■■ Cell proliferation refers to the process of increasing cell numbers by mitotic division. Cell differentiation is the process whereby a cell becomes more specialized in terms of structure and function.The periodic biochemical and structural events occurring during cell proliferation are called the cell cycle. ■■ Body cells are divided into types according to their ability to regenerate. Labile cells, such as the epithelial cells of the skin and gastrointestinal tract, are those that continue to regenerate throughout life. Stable cells, such as those in the liver, are those that normally do not divide but are capable of regeneration when confronted with an appropriate stimulus. Permanent or fixed cells are SUMMARY CONCEPTS

Collagen

Proteoglycan

Fibroblast

Hyaluronic acid

Fibronectin

Integrin

Cell membrane

FIGURE 4-3. Components of the extracellular matrix and supporting connective tissue components involved in tissue repair.

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