Journal
CELL STEM CELL
Volume 28, Issue 9, Pages 1516-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2021.04.002
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Funding
- NIH [R01HD096755]
- Burroughs-Wellcome Fund CASI Award
- NIH grant from Intestinal Stem Cell Consortium [U01DK103147]
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Allergy and Infectious Diseases
- NSF
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This study explores how intestinal organoids self-organize and generate stem cell zones (SCZs) of typical size. The size of SCZs is influenced by ion channel-mediated inflation and mechanosensitive Piezo-family channels, leading to fission through dynamic behavior. Inflation drives stem cell differentiation and induces a stretch-responsive cell state with large transcriptional changes, including upregulation of Piezo1.
How stem cells self-organize to form structured tissues is an unsolved problem. Intestinal organoids offer a model of self-organization as they generate stem cell zones (SCZs) of typical size even without a spatially structured environment. Here we examine processes governing the size of SCZs. We improve the viability and homogeneity of intestinal organoid cultures to enable long-term time-lapse imaging of multiple organoids in parallel. We find that SCZs are shaped by fission events under strong control of ion channel-mediated inflation and mechanosensitive Piezo-family channels. Fission occurs through stereotyped modes of dynamic behavior that differ in their coordination of budding and differentiation. Imaging and single-cell transcriptomics show that inflation drives acute stem cell differentiation and induces a stretch-responsive cell state characterized by large transcriptional changes, including upregulation of Piezo1. Our results reveal an intrinsic capacity of the intestinal epithelium to self-organize bymodulating and then responding to its mechanical state.
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