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The symmetry breaking event in intestinal organoids
Serra D, Mayr U, Boni A et al. Self-organization and symmetry breaking in intestinal organoid development. Nature 2019;569:66–72.
Intestinal organoids are three-dimensional structures containing multiple cell types which recapitulate the crypt-villus axis. It is unclear how a single stem cell gives rise to these complex self-organising structures. Quantitative imaging was employed to study the time course of organoid development. First, sorted LGR5+ and LGR5− cells from a fluorescently labelled mouse were used to generate organoids. LGR5+ cells had double the efficiency in forming organoids. LGR5− cells gave rise to more enterocysts, consisting ofonly enterocytes and requiring Wnt for survival. Enterocysts were thought to develop due to absence of symmetry breaking and lack of Paneth cells to produce Wnt. Time-lapse imaging showed that all organoids had identical growth patterns with symmetrical sphere-like structure up to 48 hours. After this, between the 8-cell and 16-cell stage, symmetry was broken, and new cell types emerged. RNA sequencing revealed that YAP1, a Hippo pathway effector, was transiently activated at the moment of symmetry breaking. Inhibition of YAP1 reduced organoid efficiency. YAP1 target gene expression correlated with expression of Notch ligand DLL1. Variability in nuclear YAP1 seemed to initiate a Notch-DLL1 event and cells with high nuclear YAP1 became DLL1+ cells and then Paneth cells. Gamma secretase inhibitors of Notch signalling reduced symmetry breaking and Paneth cell differentiation. In summary, YAP1 activation generates symmetry breaking and maintains enterocyte differentiation, so is vital in organoid development. YAP1 could be a sensor for tissue injury and this sheds light on its potential role in homeostasis after tissue damage, important both in inflammation and cancer.
Metastasis-associated macrophages orchestrate liver metastases from pancreatic cancer
Nielsen SR, Quaranta V, Linford A, et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol 2016;18:549–60
Pancreatic adenocarcinoma remains one of the most lethal malignancies. An understanding of the mechanisms …
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
Patient consent for publication Not required.
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