Fetal reversion from diverse lineages sustains the intestinal stem cell pool and confers stress resilience

Abstract

Plasticity is a central mechanism underlying the robust regenerative capacity of the intestinal epithelium. Two major forms of plasticity have been described: spatial plasticity, in which differentiated cells revert to crypt base columnar cells (CBCs), and fetal reversion into revival stem cells (revSCs). However, the relationship among these two stem cell populations and differentiated cells remains to be clarified. Here, we demonstrated the bidirectional interconversion between CBCs and revSCs. Using lineage tracing, injury models and villus culture, we show that absorptive enterocytes can reprogram into revSCs and regenerate CBCs. These findings position fetal reversion as an entry point to spatial plasticity, establishing a regenerative hierarchy where CBCs, revSCs, and enterocytes collectively orchestrate intestinal repair. Furthermore, we identified revSCs as a highly stress-tolerant stem cell population, whose emergence would preserve the stem cell pool. Our results establish fetal reversion as a cellular escape mechanism safeguarding epithelial regeneration under inflammatory conditions.