Abstract
Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells. Given the link between cells with stem-like properties and cancer, it is important that we identify factors that might provide a bridge between the two. Here, we identify a sub-set of chromogranin A-positive enteroendocrine cells that are positive for the developmental and cancer-associated transcription factor Brachyury in normal human small intestinal and colonic crypts. Whilst chromogranin A-positive enteroendocrine cells are also Brachyury-positive in colorectal tumours, expression of Brachyury becomes more diffuse in these samples, suggesting a more widespread function in cancer. The finding of the developmental transcription factor Brachyury in normal adult human intestinal crypts may extend the functional complexity of enteroendocrine cells and serves as a platform for assessment of the molecular processes of intestinal homeostasis that underpins our understanding of human health, cancer and aging.
Highlights
The adult intestinal epithelium is one of the most rapidly self-renewing tissues of the body, giving rise to differentiated cells for digestion and absorption of food
Brachyury marks a sub-group of nonproliferating Chromogranin A (ChgA)-enteroendocrine cells (EECs) in adult intestinal crypts
We demonstrate that strong cytoplasmic Brachyury staining is present in a small cohort of cells within the normal human colonic crypt and small intestine (Figure 2A–2E; see SI for source of ‘normal’ tissue). [Note: this strong cytoplasmic staining is very distinct from weaker cytoplasmic staining that we sometimes observed, and only strong staining is considered here]
Summary
The adult intestinal epithelium is one of the most rapidly self-renewing tissues of the body, giving rise to differentiated cells for digestion and absorption of food. The transcription factor Sox is present in the SC/progenitor zone of the mouse small intestine where it regulates proliferation and differentiation in a dose-dependent manner; Lgr5-SCs are Sox9-low, but a population of differentiated EECs expressing ChgA shows high levels of Sox. The transcription factor Sox is present in the SC/progenitor zone of the mouse small intestine where it regulates proliferation and differentiation in a dose-dependent manner; Lgr5-SCs are Sox9-low, but a population of differentiated EECs expressing ChgA shows high levels of Sox9 This latter population is Ki67-negative ( post-mitotic) but does have regenerative capacity following radiation damage [6, 7]
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