BMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes

Abstract

The intestinal epithelium possesses a remarkable self-renewal ability, which is mediated by actively proliferating Lgr5+ stem cells. Bone morphogenetic protein (BMP) signalling represents one major counterforce that limits the hyperproliferation of intestinal epithelium, but the exact mechanism remains elusive. Here we demonstrate that epithelial BMP signalling plays an indispensable role in restricting Lgr5+ stem cell expansion to maintain intestinal homeostasis and prevent premalignant hyperproliferation on damage. Mechanistically, BMP inhibits stemness of Lgr5+ stem cells through Smad-mediated transcriptional repression of a large number of stem cell signature genes, including Lgr5, and this effect is independent of Wnt/β-catenin signalling. Smad1/Smad4 recruits histone deacetylase HDAC1 to the promoters to repress transcription, and knockout of Smad4 abolishes the negative effects of BMP on stem cells. Our findings therefore demonstrate that epithelial BMP constrains the Lgr5+ stem cell self-renewal via Smad-mediated repression of stem cell signature genes to ensure proper homeostatic renewal of intestinal epithelium.

Transit-amplifying cells coordinate changes in intestinal epithelial cell-type composition

“…3b), though less so than in the EdU + stem cell network ( Supplementary Fig. 6), consistent with recent work demonstrating that BMP suppresses stem cell signature genes and, consequently, proliferation 10 . Perturbations targeting the Wnt pathway (Wnt, GSK3-i, PORCN-i) were highly connected in the TA cell network, more so than in the EdU + stem cell network, consistent with the observation that Wnt3a specifically upregulated TA cells ( Fig.…”

NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor

“…The bona fide ISC marker LGR5 is expressed exclusively at the intestinal crypt base under tight regulation, while LGR5 + ISCs are indispensable for regeneration and tumourigenesis (Metcalfe et al, 2014;de Sousa e Melo et al, 2017). Transcriptional control of LGR5 by Wnt, ASCL2 and BMP has been reported in the past (van der Flier et al, 2009;Schuijers & Clevers, 2012;Qi et al, 2017), yet the regulation of LGR5 protein turnover is largely unknown. To our knowledge, this is the first study describing the post-translational modification of LGR5 receptors via the E3 ubiquitin ligases NEDD4 and NEDD4L.…”

Untitled

“…BMP signaling limits hyper-proliferation of the intestinal epithelium and maintains differentiation along the crypt-villus axis by forming a gradient of BMPactivity where mesenchymal cells beneath the crypts express high levels of noggin whereas high levels of BMP-2 and-4 are expressed by mesenchymal cells both in the crypt and the villi [25][26][27][28]. Recent evidence has also shown that BMP-signaling constrains the selfrenewal of Lgr5+ cells via SMAD-mediated repression of the stem cell signature [29]. SMAD4 expression is frequently lost in invasive colorectal cancer, indicating that the quenching of the BMP-signaling pathway in CRC tumoroids through noggin supplementation may be less essential for successful tumoroid in vitro culture [30,31].…”