From mice to humans—divergent strategies for intestinal homeostasis and regeneration

The intestinal epithelium is maintained by stem cells that balance self‐renewal and differentiation to sustain homeostasis and enable regeneration after injury. Recent advances—including organoid culture, genome editing, orthotopic xenotransplantation, and somatic mutation–based analysis—have created new opportunities to investigate intestinal stem cell (ISC) dynamics in humans. These studies have revealed striking species‐specific differences: whereas mouse LGR5 ⁺ ISCs divide daily and are chemo‐sensitive, human colonic LGR5 ⁺ stem cells are predominantly slow‐cycling and chemo‐resistant. Consistent with this reduced cycling, human ISCs accumulate somatic mutations more slowly than those of mice. Across mammals, ISC proliferation rates inversely correlate with lifespan, a relationship thought to minimize mutation accumulation and reduce cancer risk, in line with Peto's paradox. Regenerative responses in both mice and humans can involve fetal‐like reprogramming driven by YAP and other signaling pathways, yet the extent of species differences in intestinal regenerative capacity remains unclear. This review synthesizes current insights into ISC kinetics, injury responses, and evolutionary adaptations, highlighting the need for human‐focused studies to bridge translational gaps and guide regenerative medicine strategies.