The intestinal epithelial lining rapidly renews every 4 to 5 days. The renewal is facilitated by intestinal stem cells (ISCs) located at the base of the crypt– a gland located at the bottom of each villus. ISCs divide asymmetrically to form new stem cells and progenitor daughter cells. The daughter cells are called transit-amplifying (TA) cells which move upwards along the crypt and either differentiate into absorptive cells– the enterocytes or secretory cells– including the goblet, entero-endocrine, and Paneth cells.

The differentiated cells have distinct functions. Absorptive cells or enterocytes comprise 90% of the intestinal epithelial cell population. They are involved in the absorption and transport of nutrients and electrolytes. Goblet cells secrete mucus which protects the intestinal mucosa. The enteroendocrine cells secrete hormones that help in cell proliferation and digestive activities. Paneth cells secrete antibacterial proteins such as lysozyme and are also involved in the proliferation of stem cells.

Intestinal stem cell proliferation and migration were determined using a labeling method in which radioactive thymidine was injected into the experimental mice's gut tissues. The actively dividing cells incorporate the radioactive thymidine into their DNA during S-phase. When the same cell divides, the intensity of the label gets reduced as it is distributed between the new daughter cells, which can then be quantified. Based on this experiment, it was found that the rapidly dividing cells, also known as transit-amplifying cells, are present in the middle and upper parts of the crypt, and the slowly dividing stem cells are present in the bottom part of the crypt placed between the Paneth cells. The differentiated mature epithelial cells, except for Paneth cells, are present at the finger-like projections or villi.

Two models were proposed for the identity and location of ISCs– the stem cell zone model and the +4 cell model. Cheng and Leblond proposed the stem cell zone model in which they found that stem cells are interspersed between the Paneth cells. They named these cells ‘crypt base columnar’ or CBC cells. Chris Potten and colleagues proposed the +4 stem cell model. Using the DNA labeling method, they found that these cells are located at the 4th position from the Paneth cells, hence the name ‘+4 cells’.

Recent studies have shown that the CBC cells are the ISCs that participate in renewing intestinal epithelium, whereas the +4 cells are quiescent and become activated upon injury or stress. In such cases, the +4 cells give rise to progenitor cells that eventually replace the cells damaged by stress.