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Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE115416 | GEO | 2018/08/06

REPOSITORIES: GEO

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Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.

Project description:The 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.

| S-EPMC6138952 | biostudies-literature

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration[intestine]

Project description:To define Atoh1 secretory signature, transcriptional profiling of secretory cells was performed. The expression profile of Atoh1+ cells from Atoh1(WT)CreERT2 R26RtdTom mice was determined by comparing tdTom+ (secretory) and tdTom- (absorptive) cells to define the baseline pro-secretory signature for small intestine (SI).

2018-08-06 | GSE115388 | GEO

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration [colon]

2018-08-06 | GSE115378 | GEO

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration [bulk RNA-seq]

Project description:To compare secretory signatures of wildtype and mutant mice, the transcription profiles of tdTom+ cells from Atoh1(WT)CreERT2 R26RtdTom and Atoh1(9S/T-A)CreERT2 R26RtdTom mice were generated. The profiles were obtained for both small intestine (SI) and colon.

2018-08-06 | GSE115367 | GEO

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration

Project description:Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration

| PRJNA474910 | ENA

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration[intestine]

Project description:Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration[intestine]

| PRJNA474753 | ENA

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration [colon]

Project description:Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration [colon]

| PRJNA474734 | ENA

Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration [bulk RNA-seq]

Project description:Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration [bulk RNA-seq]

| PRJNA474725 | ENA

Atoh1<sup>+</sup> secretory progenitors possess renewal capacity independent of Lgr5<sup>+</sup> cells during colonic regeneration.

Project description: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.

| S-EPMC6376326 | biostudies-literature

The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration.

Project description:Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration.

| S-EPMC5322731 | biostudies-literature

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