Intestinal Cells as Models for Apoptosis

The intestinal epithelium provides an interesting, yet complicated, model to study apoptosis. This tissue has one of the most rapid turnover rates known because cells lost to the lumen are replaced by the progeny of stem cells (Fig. 3). After division of the stem cells, one daughter cell remains anchored as the new stem cell, whereas the other undergoes several divisions in the lower and middle thirds of the crypt. Extra stem cells are eliminated by a process of spontaneous apoptosis. Each crypt produces 13-16 cells/h (19). Most of these migrate out of the crypt and onto a villus where they continue to migrate toward the villus tip. During migration, the cells mature into three of the four terminally differentiated cell types of the adult small intestinal epithelium: the absorptive enterocyte, the enteroendocrine cell, and the mucus-secreting goblet cell. A few cells migrate to the base of the crypt to become lysozyme-producing Paneth cells. Cells that migrate onto a villus are eventually shed by a process that is incompletely understood. Shedding involves apoptosis, and the question is whether the apoptosis occurs on the villus or whether it is triggered by detachment from the substrate, a process known as anoikis (20). The whole process from proliferation to shedding occurs in only 2-3 d (19). Apoptosis of dividing crypt cells can be induced by damaging agents and is dependent on the activation of Bax.

Fig. 2. Intrinsic or mitochondrial pathway. (See Subheading 2.2. for explanation and discussion.)

The intestinal epithelium of the mouse has been the primary model for studying gut apoptosis. Many of these have identified the roles of members of the Bcl-2 family of proteins and p53. Little is known of the overall regulatory process of apoptosis in the intestine, and there has been little progress in developing appropriate in vitro models of normal intestinal cells. The most widely used intestinal cell lines have been derived from tumors and are abnormal. Some, such as the popular Caco-2 line, contain a mutated p53 gene. Although all cell lines by definition have altered rates of proliferation and death, the IEC-6 line has proven useful to elucidate the pathways regulating apoptosis in untransformed crypt cells.

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