Androgen Maintains Intestinal Homeostasis by Inhibiting BMP Signaling via Intestinal Stromal Cells

Summary Research shows a higher incidence of colorectal cancer in men. However, the molecular mechanisms for this gender disparity remain unknown. We report the roles of androgen in proliferation and differentiation of intestinal stem cells via targeting of the androgen receptor (AR) on intestinal stromal cells by negatively regulating BMP signaling. Orchidectomy (ORX) or the AR antagonist promotes expansion of intestinal epithelium but suppresses intestinal stem cell (ISC) proliferation. Conversely, the AR agonist inhibits ISC differentiation but augments proliferation in ovariectomized mice. Mechanistically, activation of the AR increases expression of BMP antagonists but lowers expression of BMP4 and Wnt antagonists in primary stromal cells, which promotes intestinal organoid growth. Interestingly, the BMP pathway inhibitor LDN-193189 reverses the ORX-induced effects. Our results highlight that stromal cells constitute the intestinal stem cell niche and provide a possible explanation for higher incidence rates of colorectal cancer in men.
Highlights • Androgen receptor (AR) is expressed in intestinal stromal cells • Androgen regulates the renewal and differentiation of intestinal epithelial stem cells • Androgen regulates expression of BMP-related signal secretion in intestinal stromal cells • Selective inhibition of the BMP pathway reverses orchidectomy-induced effects
In this article, D. Chen, J. Li, and colleagues show that androgen promotes proliferation and inhibits differentiation of intestinal epithelial stem cells in mouse models. Mechanistically, they prove that activation of the androgen receptor regulates BMP-related signal secretion in intestinal stromal cells.