Abstract
SummaryThe intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of the transcription factor Atoh1 is required for both the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. As confirmed by lineage tracing, Atoh1+ cells (Atoh1(WT)CreERT2 mice) give rise to multilineage intestinal clones both in the steady state and after tissue damage. In a phosphomutant Atoh1(9S/T-A)CreERT2 line, preventing phosphorylation of ATOH1 protein acts to promote secretory differentiation and inhibit the contribution of progenitors to self-renewal. Following chemical colitis, Atoh1+ cells of Atoh1(9S/T-A)CreERT2 mice have reduced clonogenicity that affects overall regeneration. Progenitor plasticity maintains robust self-renewal in the intestinal epithelium, and the balance between stem and progenitor fate is directly coordinated by ATOH1 multisite phosphorylation.
Highlights
Within the intestinal epithelium, cell generation occurs from phenotypically heterogenous stem cells residing at the base of glandular crypts (Vermeulen and Snippert, 2014)
Mature Paneth and goblet cells were positive for the reporter whereas enteroendocrine cells (EECs) were not; the latter observation confirms that Atoh1 expression is not maintained in mature enteroendocrine cells (Bjerknes et al, 2012; Sommer and Mostoslavsky, 2014)
Atoh1(WT)CreERT2; Rosa26TdTom mice were crossed onto Lgr5Gfp reporter mice to investigate co-expression of Atoh1 and the intestinal stem cell marker Lgr5
Summary
Cell generation occurs from phenotypically heterogenous stem cells residing at the base of glandular crypts (Vermeulen and Snippert, 2014). It has been demonstrated previously that cells of the secretory lineage possess reserve stem cell function in the small intestine (SI) epithelium in homeostasis and following tissue damage (van Es et al, 2012; Ishibashi et al, 2018; Yan et al, 2017; Yu et al, 2018). Atoh1+ progenitors exhibit self-renewal and give rise to multilineage clones with higher frequency in homeostasis (Ishibashi et al, 2018) compared with previously described secretory Dll1+ progenitors (van Es et al, 2012) This observation highlights a significant contribution of Atoh1+ cells to the stem cell pool in the SI and colon. The mechanisms regulating intestinal plasticity and the nature of the relationship linking it to self-renewal remain unknown
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