Apoptosis Differently Affects Lineage Tracing of Lgr5 and Bmi1 Intestinal Stem Cell Populations

Emerging lineage-tracing data support the existence of several pools of intestinal stem cells (ISCs) in the adult mouse. The +4 location is known to harbor proliferative cells undergoing robust apoptosis in response to irradiation, but their relationship with recently reported ISC models is unclear. Here, we found that tamoxifen, at doses commonly used to induce lineage tracing, mimics the irradiation-induced apoptotic response of the +4 cells. We found that about 40% of apoptotic cells were Lgr5-positive whereas Bmi1-positive ISCs became sensitive to tamoxifen upon entering a proliferative state. In turn, when we suppressed apoptosis by either Bcl2 overexpression or Chk2 deletion, we found that lineage tracing of Lgr5-positive cells was efficiently reduced. In contrast, lineage tracing from Bmi1-positive ISCs was substantially increased in apoptosis-deficient backgrounds. We propose that apoptosis plays an important role in controlling lineage tracing from different ISC populations in the mouse intestine. ► Tamoxifen induces apoptosis of +4 cells in the mouse small intestine ► Suppression of apoptosis reduces lineage tracing from Lgr5-positive CBC cells ► Suppression of apoptosis enhances lineage tracing from Bmi1-positive ISCs ► Proliferative Bmi1 ISCs and their immediate progenitors are sensitive to tamoxifen Tamixofen-induced apoptosis skews lineage tracing from Lgr5 and Bmi1 intestinal stem cells.