Figure 2.

Cellular hierarchies and phenotypic plasticity in the intestinal epithelium during homeostasis, post-injury regeneration, and tumorigenesis. The dendrograms summarize key lineage relationships between Lgr5⁺ ISCs, transit-amplifying (TA) cells, lineage-committed precursors, terminally differentiated intestinal cell types, +4/reserve ISCs, and revival stem cells in different settings. (a) The homeostatic remodelling of the intestinal epithelium is orchestrated by niche signals that fine-tune the balance between Lgr5⁺ ISC self-renewal and differentiation. Revival stem cells are rare under homeostatic conditions (dashed boundary), and +4/reserve ISCs contribute only weakly to daily turnover during homeostasis (double-headed dashed arrow). (b) Following ablation of Lgr5⁺ ISCs post injury, +4/reserve ISCs can mobilize to replenish lost Lgr5⁺ ISCs and repopulate damaged crypts. Differentiated Lgr5⁺ progeny upregulate Clu in a YAP1-dependent manner, transiently serving as revival stem cells that can generate Lgr5⁺ ISCs de novo. Lineage-committed precursors and/or fully differentiated cells can dedifferentiate, revert to an Lgr5⁺ state, and regain stem-like traits. The transcription factor ASCL2 is critical for the ability of recent Lgr5⁺ ISC progeny to undergo dedifferentiation to an Lgr5⁺ state. Of note, Clu⁺ cells are distinct from the Lgr5⁺ and Ascl2⁺ populations. (c) Aberrant activation of Wnt signalling drives unbridled proliferation of Lgr5⁺ ISCs leading to intestinal hyperplasia. TA and differentiated cells, with hyperactive Wnt signalling and mutant KRAS^G12D, may progress to malignancy in the context of TGFβ-receptor loss or inflammation (i.e., NFκB activation). Multiple +4/reserve ISCs can also initiate tumorigenesis, and tuft cells are readily transformed by inflammation following Apc loss. Whether revival stem cells can serve as tumour-initiating cells remains unclear. Solid arrows indicate the ability to dedifferentiate and revert to a stem-like state, or the susceptibility to transformation and hyperplastic progression. Reflexive arrows indicate the ability to self-renew. Double-headed solid arrows denote dynamic interconversion between indicated cell types. Note that, to date, goblet cell progenitors have not been lineage-traced.