Immunocytochemical studies suggest two pathways for enteroendocrine cell differentiation in the colon

Enteroendocrine cells represent the most heterogeneous population of terminally differentiated cells in the mouse intestinal epithelium. Each of the approximately 15 different enteroendocrine cell subpopulations shows characteristic distributions along both the cephalocaudal and crypt-to-villus (in the small intestine) or crypt-to-surface epithelial cuff (in the colon) axes of the gut. These cells provide a sensitive model for studying how the continuously renewing gut epithelium is able to establish and maintain its spatial differentiation. Enteroendocrine cells are derived from the same multipotent stem cell that gives rise to enterocytes and goblet and Paneth cells. Regional differences in enteroendocrine cell number and type reflect positional differences in the differentiation programs of this lineage. To better understand the nature of these programs, we used multilabel immunocytochemical methods to examine the accumulation of endogenous neuroendocrine products as well as the product of a liver fatty acid binding protein/human growth hormone transgene in enteroendocrine cells located in proximal colonic glands. The results suggest that serotonin, substance P-, glucagon-like peptide-1 (GLP-1)-, peptide tyrosine tyrosine (PYY)-, neurotensin-, and cholecystokinin (CCK)-producing cells can all arise from a single stem cell located within a given gland. Based on pairwise comparison of the coexpression of each of these six products in individual cells as well as their ability to support transgene expression, it appears that the enteroendocrine lineage has two branches; one branch produces substance P and serotonin cells while the other yields GLP-1, PYY, neurotensin, and CCK cells.