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Master regulator of intestinal progenitor plasticity
Tomic G, Morrissey E, Kozar S, et al. Phospho-regulation of ATOH1 is required for plasticity of Secretory Progenitors and tissue regeneration. Cell Stem Cell 2018; 23:436–443.
Intestinal progenitor cells can be thought of as reserve stem cells which step up following tissue damage. They exhibit self-renewal and give rise to multilineage clones, thereby defining the properties of a stem cell, but are committed to intestinal lineages. It is known that transcription factor ATOH1 is upregulated in progenitors giving rise to secretory lineages, and this paper looked at the role of post-translational phosphorylation of ATOH1. An Atoh1-CreERT2 mouse model allowed lineage tracing and showed that Atoh1+ cells gave rise to Paneth, goblet cells and via an intermediate precursor, enteroendocrine cells. Radiation injury required Atoh1+ cells for cell regeneration. Atoh1 undergoes phosphorylation by cyclin-dependent kinases on multiple sites. A phosphomutant Atoh1 mouse was developed in which there was a lack of phosphorylation on all nine sites; this was phenotypically normal but showed a prosecretory shift with a reduced intestinal stem cell signature. There was impaired return of Atoh1+ cells to the stem cell compartment and thereby increased differentiation of secretory progenitors. Mathematical modelling inferred that Atoh1+ cells can repopulate the entire small bowel crypt in 1%–2% and the colonic crypt in 4%. This proportion significantly reduced in the phosphomutant mice because Atoh1+ cells were inhibited from reverting to a stem-like state. These mice exhibited reduced regeneration capacity following dextran sodium sulphate (DSS) chemical colitis, with more weight loss and slower recovery. Overall, progenitor plasticity allows an adequate response to tissue injury and ATOH1 phosphorylation is a vital step in the dynamic interplay between progenitors and stem cells.
Hepatocyte necroptosis promotes intrahepatic cholangiocarcinoma development
Seehawer M, Heinzmann F, D’Artista L, et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 2018;562:69–75.
Primary liver cancer can be classified as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma …
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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