The small intestine as a model for evaluating adult tissue stem cell drug targets

Abstract

Adult tissue stem cells are defined and some current controversies are discussed. These crucial cells are responsible for all cell production in renewing tissues, and play a vital role in tissue regeneration. Although reliable stem cell markers are generally unavailable for adult epithelial tissues, the small intestinal crypts are an excellent in vivo model system to study stem cells. Within this tissue, the stem cells have a very well-defined cell position, allowing accurate definition of stem cell specific events. Clonal regeneration assays for the small intestine allow stem cell survival and functional competence to be studied. The ultimate lineage ancestor stem cells are extremely efficiently protected from genetic damage, which accounts for the low cancer incidence in this tissue. Some of the regulatory networks governing stem and transit cell behaviour are beginning to be understood and it is postulated that p53 plays a crucial role in these processes.

Figure 1

Typical stem cell derived cell lineages. (a) A self‐maintaining stem cell (circle) divides to generate a dividing transit lineage (squares). Differentiation events generate different types of functional cells (various symbols). (b) A lineage within which the differentiation event that distinguishes transit cells from stem cells occurs after the third generation in the lineage, thus establishing a potential stem cell compartment.

Figure 2

Schematic showing the possible size of the transit cell lineages in various replacing tissues of the body (mouse). The proportional size of the stem cell compartment decreases as the lineages increase.

Figure 3

Cell lineage believed to account for cell production in the crypts of the mouse small intestine. The position of cells in the lineage can be related to position of cells on the crypt‐villus axis. A similar lineage is believed to explain cell production in the large intestinal crypt. (CP: cell position.)

Figure 4

Hypothetical role of p53 guarding the genome of stem cells in the small intestine. p53 controls damage‐induced apoptosis, asymmetric cell divisions and selective strand segregation in stem cells while directing cell‐cycle arrest and repair in transit cells.

Figure 5

Diagram illustrating the protective mechanisms operating on the small intestine stem cells.

Figure 6

Sections of mouse small intestinal crypts showing label‐retaining cells (left panel) (Potten et al. 2002a) at cell positions 4–5 and Musashi‐1 antibody staining (Potten et al. 2002b) of cells also at the same position (next panel to right). Some cells are also exquisitely sensitive to small doses of radiation and die via apoptosis (Potten 1977; Hendry et al. 1982; Potten & Grant 1998) (right‐hand panel). The second‐to‐right panel shows the cells that respond do injury (5‐fluorouracil exposure) by entering S phase at 24 h (bromodeoxyuridine labelling).

Figure 7

Part of the Delta‐Notch signalling pathway that is believed to be involved in determining asymmetric cell divisions in various developmental systems. Musashi‐1 blocks the translation of M‐Numb and is implicated in asymmetric divisions in early neural stem cells (Nakamura et al. 1994; Kaneko et al. 2000; Imai et al. 2001).

Figure 8

Schematic showing the interactions between β‐catenin/TCF and ephrins in the possible controls on differentiation and cell migration in the small intestinal crypt (Wetering van de et al. 2002; Battle et al. 2002; Booth et al. 2002).