Beyond growth signaling: Paneth cells metabolically support ISCs

Abstract

Single Lgr5 intestinal stem cells (ISCs) can be expanded in vitro into epithelial organoids or "mini-guts", self-organizing cellular structures that recreate the intestinal differentiation program; Paneth cells, which constitute the intestinal stem cell niche, secrete stem cell growth signals, and are thus essential for this process. In a recent paper published in Nature, Rodríguez-Colman et al. describe how Paneth cells may be supporting the metabolic state of ISCs.

Figure 1

(A) The intestinal epithelium is structurally organized into crypt-villus units. Stem cells and transit-amplifying cells in the crypt proliferate continuously to renew mature cells in the villi. In the crypt, Lgr5⁺ ISCs, CBCs, are intermingled with Paneth cells, differentiated and secretory cells that provide CBCs with growth signals. (B) Paneth cells are highly glycolytic. CBCs have more mitochondria than Paneth cells and have an oxidative metabolic profile. The lactate generated through glycolysis in Paneth cells is excreted and used by CBCs to drive oxidative metabolism, which supports their proliferation and differentiation. CBCs are dependent on oxidative metabolism as indicated by their sensitivity to inhibitors of oxidative phosphorylation (OXPHOS). In the schematic, orange indicates differentiated cells in villi, grey indicates transit-amplifying progenitor cells, green indicates CBCs, and brown indicates Paneth cells.