Self-organization and symmetry breaking in intestinal organoid development

• Published in: Nature (London) Vol. 569; no. 7754; pp. 66 - 72
• Main Authors: Serra, Denise, Mayr, Urs, Boni, Andrea, Lukonin, Ilya, Rempfler, Markus, Challet Meylan, Ludivine, Stadler, Michael B., Strnad, Petr, Papasaikas, Panagiotis, Vischi, Dario, Waldt, Annick, Roma, Guglielmo, Liberali, Prisca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2019; Nature Publishing Group
• Subjects: 13/106; 13/51; 14/35; 38/91; 631/1647/245/2225; 631/532/2437; 631/553/2717; 64/60; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Asymmetric structures; Broken symmetry; Calcium-Binding Proteins; Cell Cycle Proteins; Crypts; DELTA protein; Gene expression; Humanities and Social Sciences; Intercellular Signaling Peptides and Proteins - metabolism; Intestine; Intestines; Intestines - cytology; Mice; multidisciplinary; Observations; Organoids; Organoids - cytology; Organoids - growth & development; Organoids - metabolism; Paneth cells; Paneth Cells - cytology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Physiological aspects; Receptors, G-Protein-Coupled - metabolism; Regeneration; Science; Science (multidisciplinary); Single-Cell Analysis; Spheres; Stem cells; Symmetry; Symmetry (Biology); Transcription activation; YAP-Signaling Proteins; Yes-associated protein; United States > US
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-1146-y

Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the self-organizing ability of cell populations derived from a single intestinal stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which generate the stem-cell niche and lead to asymmetric structures such as the crypts and villi. Here we combine single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. We show that their development follows a regeneration process that is driven by transient activation of the transcriptional regulator YAP1. Cell-to-cell variability in YAP1, emerging in symmetrical spheres, initiates Notch and DLL1 activation, and drives the symmetry-breaking event and formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures. Single-cell-based imaging and sequencing approaches are used to characterize organoid development and the intestinal regeneration process, which is driven by transient activation of YAP1.