Figure 1.

Stem-cell dynamics during intestinal homeostasis and regeneration. (A) Under homeostatic conditions, Wnt-driven Lgr5⁺ ISCs maintain epithelial turnover. Following injury, Lgr5⁺ ISCs are lost or reprogrammed, while lineage-committed progenitors adopt a Yap-dependent fetal signature and give rise to de novo Lgr5⁺ ISCs. (B) Multiple roads repopulate Lgr5⁺ ISCs. Various regenerative stem-cell populations have been described to date and may represent distinct dedifferentiation processes involved in gut regeneration. RevSCs [55] and wound-associated epithelial cells (WAE cells) [59] express several markers of the pseudostratified fetal gut epithelium and, thus, may represent equivalent cell types. Hopx⁺ cells have been shown to co-express the fetal marker Trop2 (Tacsdtd2), while Ascl2⁺ cells are devoid of fetal markers. (C) Single-road model of Lgr5⁺ ISC replenishment. As an alternative scenario, we postulate that, under the influence of Yap signaling, revSCs are the earliest dedifferentiating cell type that may ultimately give rise to Hopx⁺ and/or Ascl2⁺ cells, which acquire progressively more homeostatic features. During this process, fetal and homeostatic stem-cell genes would mark early and late stages of regeneration, respectively. Figure was prepared using Biorender.com.