Interplay between metabolic identities in the intestinal crypt supports stem cell function

Abstract

The small intestinal epithelium self-renews every four or five days. Intestinal stem cells (Lgr5 crypt base columnar cells (CBCs)) sustain this renewal and reside between terminally differentiated Paneth cells at the bottom of the intestinal crypt. Whereas the signalling requirements for maintaining stem cell function and crypt homeostasis have been well studied, little is known about how metabolism contributes to epithelial homeostasis. Here we show that freshly isolated Lgr5 CBCs and Paneth cells from the mouse small intestine display different metabolic programs. Compared to Paneth cells, Lgr5 CBCs display high mitochondrial activity. Inhibition of mitochondrial activity in Lgr5 CBCs or inhibition of glycolysis in Paneth cells strongly affects stem cell function, as indicated by impaired organoid formation. In addition, Paneth cells support stem cell function by providing lactate to sustain the enhanced mitochondrial oxidative phosphorylation in the Lgr5 CBCs. Mechanistically, we show that oxidative phosphorylation stimulates p38 MAPK activation by mitochondrial reactive oxygen species signalling, thereby establishing the mature crypt phenotype. Together, our results reveal a critical role for the metabolic identity of Lgr5 CBCs and Paneth cells in supporting optimal stem cell function, and we identify mitochondria and reactive oxygen species signalling as a driving force of cellular differentiation.

Defining the role of Lgr5+ stem cells in colorectal cancer: from basic research to clinical applications

“…As one of the niche components, terminally differentiated Paneth cells located adjacent to Lgr5 + ISCs support Lgr5 + ISCs by secreting niche ligands. In addition to this juxtacrine interaction, by using organoids and metabolomics Rodriguez-Colman et al recently discovered that Paneth cells can also control ISC fate by dynamically supporting Lgr5 + ISC metabolism [10]. Specifically, they found that oxidative phosphorylation is distinctly active and essential in mature Lgr5 + ISCs and that glycolytic Paneth cells support oxidative Lgr5 + ISCs by supplying lactate.…”

Metabolic traits of cancer stem cells

“…For example, in intestinal crypts (Box 1), Lgr5 + SCs have increased OXPHOS, whereas Paneth cells (Box 1) preferentially use glycolysis. Paneth cells regulate the renewal of Lgr5 + SCs by producing lactate for the oxidative metabolism of the SCs (Rodríguez-Colman et al, 2017). Apparently, high ROS levels are not harmful to intestinal SCs, but rather induce their differentiation (Yilmaz et al, 2012; Rodríguez-Colman et al, 2017).…”

“…Paneth cells regulate the renewal of Lgr5 + SCs by producing lactate for the oxidative metabolism of the SCs (Rodríguez-Colman et al, 2017). Apparently, high ROS levels are not harmful to intestinal SCs, but rather induce their differentiation (Yilmaz et al, 2012; Rodríguez-Colman et al, 2017). Another example is satellite muscle cells (Box 1), which are localized in aerobic niches and use mainly OXPHOS; in contrast, committed progenies of these SCs undergo epigenetic reprogramming consistent with a shift to glycolytic metabolism (Ryall et al, 2015).…”

Lymphocyte Fate and Metabolism: A Clonal Balancing Act

“…Recent examination of several regenerative systems, including lymphocytes and mammary, hematopoietic, muscle, intestinal, and neural stem cells has begun to suggest that autophagy or elimination of older mitochondria, biogenesis and fusion of new organelle, along with efficient oxidative metabolism and low ROS levels are critical processes for self-renewal and cellular quiescence [2, 11, 14, 15, 18, 19, 55-57]. Reciprocally, mitochondrial stasis, aerobic glycolysis, and ROS production have been associated with greater activation, differentiation and cellular senescence.…”