[HTML][HTML] Keratinocyte stem cells: targets for cutaneous carcinogens

RJ Morris - The Journal of clinical investigation, 2000 - Am Soc Clin Investig
RJ Morris
The Journal of clinical investigation, 2000Am Soc Clin Investig
The epidermis is a continually renewing tissue, normally balancing cellular proliferation in
the basal layer with loss from the suprabasal layer through a process of terminal
differentiation (for reviews, see refs. 5, 7). The basal layer in adult mice consists primarily of
keratinocytes, although Langerhans cells (representing about 10% of the cells in this layer)
and melanocytes (about 3%) can also be found, as can a small number of special sensory
cells, Merkel cells. Hair follicles (shown in Figure 1) are specialized cutaneous appendages …
The epidermis is a continually renewing tissue, normally balancing cellular proliferation in the basal layer with loss from the suprabasal layer through a process of terminal differentiation (for reviews, see refs. 5, 7). The basal layer in adult mice consists primarily of keratinocytes, although Langerhans cells (representing about 10% of the cells in this layer) and melanocytes (about 3%) can also be found, as can a small number of special sensory cells, Merkel cells. Hair follicles (shown in Figure 1) are specialized cutaneous appendages, contiguous with both the interfollicular epidermis and the sebaceous glands.
Although at first glance the basal epidermal cells of mice appear microscopically quite uniform, more careful investigation of whole mounts of epidermal sheets and vertical cross sections through the dorsal epidermis of the mouse shows that this tissue is organized into morphologically defined proliferative units (Figure 2). Well prepared vertical cross sections reveal a single layer of basal cells covered with a suprabasal layer consisting of regularly spaced columns of three flattened nucleated cells and occasional cells between the columns (Figure 2a). Epidermal proliferative units, most easily visualized in silver-stained epidermal whole mounts, contain groups of 10–12 basal cells positioned in a spiral pattern within the margins of the flattened suprabasal cells (Figure 2b). Two or three of the basal cells in each group are close to the central column of suprabasal nuclei. The remaining, peripheral basal cells in each proliferative unit are usually more than one nuclear diameter from the center. The mitotic activities of these central and peripheral cells are quite distinct. Epidermal DNA synthesis and mitosis vary in a circadian manner, with the morning hours marking the peak of mitotic activity, and the evening hours marking the peak of DNA synthesis. Following a single injection of [3H] thymidine in the morning hours, about 5% of the nuclei in peripheral cells take up the label and are visible in light microscopic autoradiographs. Nuclei in the central cells do not become labeled after this brief exposure. Mitotic figures are also easy to find among the peripheral nuclei but are rarely seen in the central cells, indicating that most of the cell division among basal keratinocytes occurs in the periphery of these proliferative units. Although occasional cells with pulse-labeled nuclei remain on the basal layer for a month or more, these cells typically remain on the basal layer for only 4 to 5 days before they are displaced to the suprabasal layers and are found in the columns. Hence, these pulselabeled cells behave as though they were more mature or more differentiated than the central basal cells. Although nuclei of central cells are not readily labeled by a short pulse of [3H] thymidine, they can be labeled by exposure to [3H] thymidine for a week or more, suggesting that they cycle far more slowly than peripheral cells. This suggestion was borne out by the work of Bickenbach and Mackenzie (8, 9), and shortly thereafter by Potten (10) and this laboratory (11). Different labeling methods and different ages of mice were used, but with similar results: When the entire basal layer is labeled by
The Journal of Clinical Investigation