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

events leading to mitosis, including DNA replication and assembly of the mitotic spindle. Although each phase of the cell cycle is monitored carefully, the transition from G 2 to M is believed to be one of the most important checkpoints in the cell cycle. In addition to the synthesis and degradation of the cyclins, the cyclin–CDK com- plexes are regulated by the binding of CDK inhibitors. The CDK inhibitors are particularly important in regu- lating cell cycle checkpoints during which mistakes in DNA replication are repaired. The finding that the cell cycle can be reactivated by removing CDK inhibitors in quiescent and nonproliferating cells has potential impli- cations for tissue repair and cell replacement therapy. 4 Proliferative Capacity ofTissues The capacity for regeneration varies with the tissue and cell type. Body tissues are divided into three types depending on the ability of their cells to undergo regen- eration: (1) continuously dividing, (2) stable, and (3) permanent tissues. 1,2 Continuously dividing or labile tissues are those in which the cells continue to divide and replicate through- out life, replacing cells that are continually being destroyed. They include the surface epithelial cells of the skin, oral cavity, vagina, and cervix; the columnar epithelium of the gastrointestinal tract, uterus, and fal- lopian tubes; the transitional epithelium of the urinary tract; and bone marrow cells. These tissues can readily regenerate after injury as long as a pool of stem cells is preserved. Bleeding, for example, stimulates the rapid proliferation of replacement cells by the blood-forming progenitor cells of the bone marrow. Stable tissues contain cells that normally stop divid- ing when growth ceases. Cells in these tissues remain quiescent in the G 0 stage of the cell cycle. However, these cells are capable of undergoing regeneration when confronted with an appropriate stimulus; thus, they are capable of reconstituting the tissue of origin. Stable cells constitute the parenchyma of solid organs such as the liver and kidney. They also include smooth muscle cells, vascular endothelial cells, and fibroblasts, the pro- liferation of which is particularly important to wound healing. The cells in permanent tissues do not proliferate. The cells in these tissues are considered to be terminally differentiated and do not undergo mitotic division in postnatal life. The permanent cells include nerve cells, skeletal muscle cells, and cardiac muscle cells. These cells do not normally regenerate; once destroyed, they are replaced with fibrous scar tissue that lacks the func- tional characteristics of the destroyed tissue. Stem Cells Another type of tissue cell, called a stem cell, remains incompletely differentiated throughout life. 1,2,5 In most continuously dividing tissues, the mature cells are ter- minally differentiated and short lived. As mature cells die the tissue is replenished by the differentiation of cells

Dividing stem cell

Stem cell

Progenitor cell

Daughter cells

Differentiated cells

generated from stem cells. Stem cells are reserve cells that remain quiescent until there is a need for cell replenish- ment, in which case they divide, producing other stem cells and cells that can carry out the functions of the dif- ferentiated cell. When a stem cell divides, one daughter cell retains the stem cell characteristics, and the other daughter cell becomes a progenitor cell that undergoes a process that leads to terminal differentiation (Fig. 4-2). Stem cells are characterized by three important prop- erties: self-renewal, asymmetric replication, and differ- ential potential. 1,2 Self-renewal means that the stem cells can undergo numerous mitotic divisions while main- taining an undifferentiated state. Asymmetric replica- tion means that after each cell division, some progeny of the stem cell enter a differentiation pathway, while oth- ers remain undifferentiated, retaining their self-renewal capacity. The progeny of each progenitor cell follows a more restricted genetic program, with the differentiating cells undergoing multiple mitotic divisions in the process of becoming a more mature cell type, and with each gen- eration of cells becoming more specialized. In this way, a single stem cell can give rise to the many cells needed for normal tissue repair or blood cell production. The term potency is used to define the differentia- tion potential of stem cells. Totipotent stem cells are those produced by a fertilized ovum. The first few cells produced after fertilization are totipotent and can dif- ferentiate into embryonic and extraembryonic cells. Totipotent stem cells give rise to pluripotent stem cells that can differentiate into the three germ layers of the embryo. Multipotent stem cell s are cells such as hema- topoietic stem cells that give rise to a family of cells, including the red blood cells and all the various types of leukocytes. Finally, unipotent stem cells produce only one cell type but retain the property of self-renewal. FIGURE 4-2. Mechanisms of stem cell–mediated cell replacement. Division of a stem cell with an unlimited potential for proliferation results in one daughter cell, which retains the characteristics of a stem cell, and a second daughter cell that differentiates into a progenitor or parent cell, with limited potential for differentiation and proliferation. As the daughter cells of the progenitor cell proliferate they become more differentiated, until they reach the stage where they are fully differentiated.

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