Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

cells, that can differentiate into the different cell types throughout life.

Tissue stem cell

The Cell Cycle In order to understand cell proliferation, whether physi- ologic (as in tissue regeneration and repair) or patho- logic (as in cancer), it is important to learn about the cell cycle, an orderly sequence of events in which a cell duplicates its genetic contents and divides. During the cell cycle, the duplicated chromosomes are appropri- ately aligned for distribution between two genetically identical daughter cells. The cell cycle is divided into four distinct phases referred to as G 1 , S, G 2 , and M. Gap 1 (G 1 ) is the post- mitotic phase during which deoxyribonucleic acid (DNA) synthesis ceases while ribonucleic acid (RNA) and protein synthesis and cell growth take place (see Understanding the Cell Cycle). 1–4 During the S phase, DNA synthesis occurs, giving rise to two separate sets of chromosomes, one for each daughter cell. G 2 is the premitotic phase and is similar to G 1 in that DNA syn- thesis ceases while RNA and protein synthesis continue. Collectively, G 1 , S, and G 2 are referred to as interphase . The M phase is the phase of nuclear division and cyto- kinesis. Continually dividing cells, such as the stratified squamous epithelium of the skin, continue to cycle from one mitotic division to the next. When environmental conditions are adverse, such as nutrient or growth fac- tor unavailability, or cells become terminally differenti- ated (i.e., highly specialized), cells may exit the cell cycle, becoming mitotically quiescent and reside in a special resting state known as G 0 . Cells in G 0 may reenter the cell cycle in response to extracellular nutrients, growth factors, hormones, and other signals such as blood loss or tissue injury that trigger cell renewal. Highly special- ized and terminally differentiated cells, such as neurons, may permanently stay in G 0 . Within the cell cycle are checkpoints where pauses or arrests can be made if the specific events in the phases of the cell cycle have not been completed. There are also opportunities for ensuring the accuracy of DNA repli- cation. These DNA damage checkpoints allow for any defects to be edited and repaired, thereby ensuring that each daughter cell receives a full complement of genetic information, identical to that of the parent cell. 1–3 The cyclins are a family of proteins that control the entry and progression of cells through the cell cycle. 1–4 Cyclins bind to (thereby activating) proteins called cyclin-dependent kinases (CDKs). Kinases are enzymes that phosphorylate proteins. The CDKs phosphorylate specific target proteins and are expressed continuously during the cell cycle but in an inactive form, whereas the cyclins are synthesized during specific phases of the cell cycle and then degraded once their task is completed. Different arrangements of cyclins and CDKs are associ- ated with each stage of the cell cycle. For example, cyclin B and CDK1 control the transition from G 2 to M. As the cell moves into G 2 , cyclin B is synthesized and binds to CDK1. The cyclin B–CDK1 complex then directs the

Differentiation

terms of structure and function. 1,2 Stem cells are undif- ferentiated cells that have the capacity to generate mul- tiple cell types (to be discussed). In normal tissue the size of the cell population is determined by a balance of cell proliferation, death by apoptosis (see Chapter 2), and emergence of newly differentiated cells from stem cells 2 (Fig. 4-1). Several cell types proliferate during tis- sue repair including remnants of injured parenchymal tissue cells, vascular endothelial cells, and fibroblasts. The proliferation of these cell types is driven by proteins called growth factors . The production of growth fac- tors and the ability of these cells to respond and expand in sufficient numbers are important determinants of the repair process. All of the different cell types in the body originate from a single cell—the fertilized ovum. As the embry- onic cells increase in number, they differentiate, facili- tating the development of all the different cells and organs of the body. The process of differentiation is regulated by a combination of internal processes involv- ing the expression of specific genes and external stimuli provided by neighboring cells, the ECM, and a variety of growth factors. The process occurs in orderly steps, with each progressive step being exchanged for a loss of ability to develop different cell characteristics. As a cell becomes more highly specialized, the stimuli that are able to induce mitosis become more limited. Neurons, which are highly specialized cells, lose their ability to proliferate once development of the nervous system is complete. In other, less-specialized tissues, such as the skin and mucosal lining of the gastrointestinal tract, a high degree of cell renewal continues throughout life. Even in these continuously renewing cell populations, the more specialized cells are unable to divide. Many of these cell populations rely on progenitor or parent cells of the same lineage. Progenitor cells are sufficiently differentiated so that their daughter cells are limited to the same cell line, but they have not reached the point of differentiation that precludes the potential for active proliferation. Some cell populations have self-renewing multipotent stem cells, such as the epithelial stem Cell proliferation FIGURE 4-1. In normal tissues, the size of the cell population is determined by a balance of cell proliferation, death by apoptosis, and emergence of newly differentiated cells from stem cells. Apoptosis Cell population