Fig. 2.

Reserve intestinal stem cell (rISC) model vs. plasticity mechanism. Exposure to irradiation or chemotherapeutic agents eliminates actively proliferating cells, including crypt base columnar cells (CBCs) and transit-amplifying (TA) cells. In response to DNA damage, rISCs (Lgr5^lo) enter the cell cycle to replenish active ISCs (Lgr5^hi) and epithelial cells. In addition, some reports demonstrate that Lgr5^lo cells above the crypt, potentially derived from the Lgr5^hi CBCs, can resist DNA damage-induced cell death and contribute to regeneration. Furthermore, in genetic-induced ISCs, depletion settings in which ISCs, including both Lgr5^hi and Lgr5^lo subsets, are eliminated with diphtheria toxin (*), progenitors of either enterocyte or secretory lineages, and even transit-amplifying cells can reprogram to ISCs and support regeneration. This is termed the plasticity model. Lgr5, leucine-rich repeat-containing G protein-coupled receptor 5; LRC, label-retaining cell; Alpi-CreER, alkaline phosphatase, intestinal-Cre recombinase; Atoh1, protein atonal homolog 1; Dil1, dynein intermediate light chain 1.