Shifting paradigms in tissue stem cell biology: Insights from the intestine

The small intestinal epithelium represents the most rapidly self-renewing adult mammalian tissue, with a turnover time of 1-2 weeks. It contains ∼12 easily recognizable cell types with a wide diversity of functions, including nutrient absorption, mucus production, antimicrobial defense, and the regulation of metabolism by incretins like Glp1. The simple and repetitive crypt-villus architecture allows for easily interpretable experimentation in transgenic mice in vivo, while the human stem cell hierarchy is experimentally accessible in epithelial organoids in vitro. This review aims to comprehensively describe the design, the cellular constituents, and the molecular regulation of crypt-villus epithelial self-renewal. More generally, it highlights deviations from commonly held views on tissue stem cell biology: gut stem cells divide continually and symmetrically. They can be expanded indefinitely in vitro, while the plasticity of daughter cells can recreate stem cells during regeneration.