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

Abstract

During homeostasis, the colonic epithelium is replenished every 3–5 days by rapidly cycling Lgr5+ stem cells. However, various insults can lead to depletion of Lgr5+ stem cells, and colonic epithelium can be regenerated from Lgr5‐negative cells. While studies in the small intestine have addressed the lineage identity of the Lgr5‐negative regenerative cell population, in the colon this question has remained unanswered. Here, we set out to identify which cell(s) contribute to colonic regeneration by performing genetic fate‐mapping studies of progenitor populations in mice. First, using keratin‐19 (Krt19) to mark a heterogeneous population of cells, we found that Lgr5‐negative cells can regenerate colonic crypts and give rise to Lgr5+ stem cells. Notch1+ absorptive progenitor cells did not contribute to epithelial repair after injury, whereas Atoh1+ secretory progenitors did contribute to this process. Additionally, while colonic Atoh1+ cells contributed minimally to other lineages during homeostasis, they displayed plasticity and contributed to epithelial repair during injury, independent of Lgr5+ cells. Our findings suggest that promotion of secretory progenitor plasticity could enable gut healing in colitis.

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

“…In support of this notion, another study demonstrated that NEUROG3+ cells not only give rise to EECs but surprisingly also to non-EEC cells, which suggests these progenitors can dedifferentiate to produce other lineages (Schonhoff et al, 2004). Additional recent studies have shown that ATOH1+ common secretory progenitors can dedifferentiate into a multipotent stem-like state spontaneously and in response to intestinal injury (Tomic et al, 2018) (Castillo-Azofeifa et al, 2019. In agreement with these studies our trajectory analyses predict that while the vast majority of EEC progenitors are stable, a small fraction is predicted to dedifferentiate.…”

Arachidonic Acid Promotes Intestinal Regeneration by Activating WNT Signaling

“…Indeed, cellular plasticity has been proved in several lineages residing above the crypt base and contributes to intestinal regeneration. Dll1 + or Atoh1 + secretory progenitors and Alpi + enterocyte progenitors have been shown to possess renewal capacity and were able to compensate for the complete ablation of Lgr5 + cells under physiological or regenerative conditions ( Castillo-Azofeifa et al., 2019 ; Tetteh et al., 2016 ; van Es et al., 2012 ). Another recent study showed that the post-IR regeneration of intestinal epithelium preferentially went through the activation of crypt Clu + cells rather than the recruitment of depleted Lgr5 + cells ( Ayyaz et al., 2019 ).…”

Intestinal epithelial plasticity and regeneration via cell dedifferentiation

“…Interestingly, distinguished from the slow-cycling Hopx + stem cells that display a constant Hopx expression identified by Takeda et al, Hopx + CARSCs display a transient discontinuation of Hopx expression upon injury and then proliferate to reestablish the colon architecture. The secretory progenitor cells marked by the transcription factor Atoh1 have also been shown to repopulate the colonic epithelium during DSS-induced colitis (Castillo-Azofeifa et al 2019 ; Ishibashi et al 2018 ; Tomic et al 2018 ). Therefore, it would be interesting to know if Atoh1 + progenitors overlap with Hopx + CARSCs.…”