Fig. 2.

Dedifferentiation of +4 active reserve enterochromaffin cells (arECs) into actively cycling intestinal stem cells (aISCs). A: cartoon model of +4 enterochromaffin (EC)-originated generation of intestinal epithelium based on tryptophan hydroxylase 1 (TPH1) lineage-tracing studies. Following asymmetric division, a +4 EC cell dedifferentiates into an aISC and becomes subjected to neutral drift selection. Once selected, the +4 EC-originated aISC dominates the ISC population in the crypt and contributes to the generation of the epithelium. This specific subset of +4 EC cells that undergo dedifferentiation to become an aISC is termed a +4 active reserve EC cell (+4 arEC) in the text. B: Left, representative image of an asymmetric division of a TPH1-derived Tomato (orange)-labeled +4 EC cell [chromogranin (ChgA)⁺, basal side] initiating the subsequent formation of an aISC (ChgA⁻, luminal side). Middle, a computational simulation of lineage-tracing experimental data shows the time-dependent increase in Tomato-labeled ribbon formations in the small intestine following tamoxifen induction (12 mice with 600 initial +4 EC clones) that supports a neutral drift model of +4 EC cell-originated aISCs. Right, representative image of a TPH1-derived Tomato-expressing ribbon formation that originated from a Tomato-positive crypt.