Download Metabolic interplay in the stem cell niche of the small intestine

Metabolic interplay in the stem cell niche of the small intestine
Boudewijn MT Burgering, UMC Utrecht
The small intestinal epithelium self-renews every 4–5 days. Intestinal stem cells (Lgr5+CBCs crypt
based columnar cells) sustain this renewal and reside between terminally differentiated Paneth cells
(PCs) at the bottom of the intestinal crypt. The ability to grow in vitro small intestinal organoids that
recapitulate all cel types of the organ in vivo enables detailed analysis of stem cell function in the
context of its niche. The signalling requirements for maintaining stem cell function and crypt
homeostasis are well studied, yet little is known how metabolism contributes to epithelial homeostasis.
Interestingly freshly isolated Lgr5+CBCs and PCs from mouse small intestine display different
metabolic programs. Compared to PCs, Lgr5+CBCs display high mitochondrial activity. Inhibition of
mitochondrial activity in Lgr5+CBCs or inhibition of glycolysis in PCs, strongly affects stem cell
function as indicated by impaired organoid formation. In addition PCs support stem cell function by
providing lactate to sustain the enhanced mitochondrial oxidative phosphorylation (OXPHOS) in the
Lgr5+CBCs. Mechanistically OXPHOS stimulates p38 MAPK activation by mitochondrial reactive
oxygen species (ROS) signalling thereby establishing the mature crypt phenotype. This initial study
revealed not only a critical role for the metabolic identity ofLgr5+CBCs and PCs in supporting optimal
stem cell function, but also identify mitochondria and ROS signalling as a driving force of cellular
differentiation. We are now extending this paradigm into several new directions to answer questions
such as the role of the micro biome and specific diets in regulating stem cell function; but also how
pathways such as known metabolic regulators like the PI3K pathway affect stem cell function.