Contribution of ATOH1+ Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium

Abstract

SummaryATOH1 is a master transcription factor for the secretory lineage differentiation of intestinal epithelial cells (IECs). However, the comprehensive contribution of ATOH1+ secretory lineage IECs to the homeostasis, repair, and tumorigenesis of the intestinal epithelium remains uncertain. Through our ATOH1+ cell-lineage tracing, we show here that a definite number of ATOH1+ IECs retain stem cell properties and can form ATOH1+IEC-derived clonal ribbons (ATOH1+ICRs) under completely homeostatic conditions. Interestingly, colonic ATOH1+ IECs appeared to exhibit their stem cell function more frequently compared with those of the small intestine. Consistently, the formation of ATOH1+ICRs was significantly enhanced upon dextran sodium sulfate colitis-induced mucosal damage. In addition, colonic ATOH1+ IECs acquired tumor stem cell-like properties in the azoxymethane-DSS tumor model. Our results reveal an unexpected contribution of colonic ATOH1+ IECs to maintaining the stem cell population under both homeostatic and pathologic conditions and further illustrate the high plasticity of the crypt-intrinsic stem cell hierarchy.

Atoh1 + secretory progenitors possess renewal capacity independent of Lgr5 + cells during colonic regeneration

“…Our observations are consistent with the recent findings reported by two other groups demonstrating that Atoh1 + secretory cells are able to contribute to colonic regeneration post-colitis (Ishibashi et al, 2018;Tomic et al, 2018). Our findings demonstrate that Notch1 + absorptive progenitors do not play a role in colonic epithelial repair, whereas Atoh1 + secretory cells proliferate and expand to contribute to epithelial regeneration during colitis.…”

“…Upon injury, however, both colonic and intestinal Atoh1 + cells expand to renew the epithelium, consistent with plasticity required for crypt regeneration. Our observations are consistent with the recent findings reported by two other groups demonstrating that Atoh1 + secretory cells are able to contribute to colonic regeneration post-colitis (Ishibashi et al, 2018;Tomic et al, 2018). Thus, a subset of Atoh1 + cells in the colon can renew the epithelium during normal homeostasis, whereas in the small intestine, Atoh1 + cells behave similarly to intestinal Dll1 + progenitors cells that are short-lived and only lineage trace upon epithelial injury (van Es et al, 2012).…”

“…post-tamoxifen, by 30 days post-tamoxifen this increased to~20% of total colonic crypts ( Fig EV3A and B). This finding suggests that the Atoh1 + cell population may overlap with the stem cell population during homeostasis, as previously shown in the small intestine (Kim et al, 2016;Ishibashi et al, 2018). In the setting of DSS colitis, day 12 lineage tracing of entire colonic crypts from Atoh1 + cells remained unchanged from control mice without colitis ( Fig 4A and B).…”

“…These data point to cellular plasticity in the intestinal epithelium, and, in particular, to the ability of more differentiated cells to revert to a stem cell fate within the crypt (Fre et al, 2011;Furuyama et al, 2011;Montgomery et al, 2011;Takeda et al, 2011;Powell et al, 2012). Notably, we and others have also reported that Lgr5 + stem cells are highly sensitive to epithelial injury induced by radiation or colitis Asfaha et al, 2015;Ishibashi et al, 2018), suggesting that an Lgr5negative cell population is responsible, at least in part, for colonic regeneration. More recently, work by two groups suggested that secretory cells marked by the transcription factor Atoh1 contribute to colonic epithelial repair (Ishibashi et al, 2018 andTomic et al, 2018).…”

“…Notably, we and others have also reported that Lgr5 + stem cells are highly sensitive to epithelial injury induced by radiation or colitis Asfaha et al, 2015;Ishibashi et al, 2018), suggesting that an Lgr5negative cell population is responsible, at least in part, for colonic regeneration. More recently, work by two groups suggested that secretory cells marked by the transcription factor Atoh1 contribute to colonic epithelial repair (Ishibashi et al, 2018 andTomic et al, 2018). However, neither study directly addressed whether Atoh1 + cells are dependent on Lgr5 + stem cells for this epithelial repair.…”