The ability of tissues to repair themselves is determined, in part, by their intrinsic proliferative capacity. In some tissues (sometimes called labile tissues), cells are constantly being lost and must be continually replaced by new cells that are derived from tissue stem cells and rapidly proliferating immature progenitors. These types of tissues include hematopoietic cells in the bone marrow and many surface epithelia, such as the basal layers of the squamous epithelia of the skin, oral cavity, vagina, and cervix; the cuboidal epithelia of the ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract); the columnar epithelium of the gastrointestinal tract, uterus, and fallopian tubes; and the transitional epithelium of the urinary tract. These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.
Other tissues (called stable tissues) are made up of cells that are normally in the G0 stage of the cell cycle and hence not proliferating, but they are capable of dividing in response to injury or loss of tissue mass. These tissues include the parenchyma of most solid organs, such as liver, kidney, and pancreas. Endothelial cells, fibroblasts, and smooth muscle cells are also normally quiescent but can proliferate in response to growth factors, a reaction that is particularly important in wound healing.
Some tissues (called permanent tissues) consist of terminally differentiated nonproliferative cells, such as the majority of neurons and cardiac muscle cells. Injury to these tissues is irreversible and results in a scar, because the cells cannot regenerate. Skeletal muscle cells are usually considered nondividing, but satellite cells attached to the endomysial sheath provide some regenerative capacity for muscle.
Cell proliferation is driven by signals provided by growth factors and from the extracellular matrix. Many different growth factors have been described, some of which act on multiple cell types, while others are cell-type specific (Chapter 1). Growth factors are typically produced by cells near the site of damage. The most important sources of these growth factors are macrophages that are activated by the tissue injury, but epithelial and stromal cells also produce some of these factors. Several growth factors bind to ECM proteins and are displayed at the site of tissue injury at high concentrations. All growth factors activate signaling pathways that ultimately induce changes in gene expression that drive cells through the cell cycle and support the biosynthesis of molecules and organelles that are needed for cell division (Chapter 1). In addition to responding to growth factors, cells use integrins to bind to ECM proteins, and signals from the integrins can also stimulate cell proliferation.
In the process of regeneration, proliferation of residual cells is supplemented by development of mature cells from stem cells. In Chapter 1 we introduced the major types of stem cells. In adults, the most important stem cells for regeneration after injury are tissue stem cells. These stem cells live in specialized niches, and it is believed that injury triggers signals in these niches that activate quiescent stem cells to proliferate and differentiate into mature cells that repopulate the injured tissue.
Mechanisms of Tissue Regeneration
The importance of regeneration in the replacement of injured tissues varies in different types of tissues and with the severity of injury.
• In epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation of residual cells and differentiation of cells derived from tissue stem cells, providing the underlying basement membrane is intact. The residual epithelial cells produce the growth factors involved in these processes. The newly generated cells migrate to fill the defect created by the injury, and tissue integrity is restored (