Immunohistochemical studies indicate multiple enteroendocrine cell differentiation pathways in the mouse proximal small intestine

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Abstract
The enteroendocrine cell system of the mammalian gastrointestinal tract is comprised of at least 16 different subpopulations. Each subpopulation shows a characteristic distribution along both the crypt-villus and cephalocaudal axes. In both the small intestine and colon of adult mice, multilabel immunohistochemistry has demonstrated that two or more neuroendocrine products can be coexpressed in various combinations in single cells along the crypt-villus axis, suggesting that enteroendocrine phenotypes may be actively regulated. Using bromodeoxyuridine (BrdU) incorporation and multilabel immunohistochemistry, we have previously demonstrated an enteroendocrine cell differentiation pathway consisting of two subpopulations of cells in the mouse proximal small intestine—one involving the sequential expression of substance P, serotonin, and secretin in cells migrating out of the crypts into the villi, and a second involving the expression of substance P and serotonin in cells which remain in the crypts. In this report, we use double label immunohistochemistry and BrdU incorporation to define the temporal and spatial interrelationships between gastrin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) immunoreactive cells in the mouse proximal small intestine. The expression of these products was compared with that of substance P, serotonin, and secretin. Minimal overlap of expression was found in cells immunoreactive for substance P or serotonin with gastrin, CCK, GLP-1, or GIP; however, secretin was found colocalized in villus-associated gastrin, CCK, and GLP-1 containing cells. We demonstrate that, similar to the bidirectionally migrating substance P and serotonin expressing cells, gastrin, CCK, GLP-1, and secretin are expressed in upwardly migrating cells, and gastrin, CCK, and GLP-1 are expressed in downwardly migrating cells that fail to express secretin. GIP containing cells only rarely coexpressed any of the products examined, but were found both in the villi and the crypts, suggesting both upwardly and downwardly migrating populations. These findings demonstrate several novel enteroendocrine cell differentiation pathways. In addition, the expression of secretin in the villi, but not in the crypts, by two otherwise distinct differentiation pathways, and the lack of secretin expression by villus-associated GIP expressing cells, suggests that local factors present in the crypts and/or on the villi are necessary, but not sufficient, for secretin expression.

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