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An image-based systems biology approach to symmetry breaking in collective cell behavior.

English title An image-based systems biology approach to symmetry breaking in collective cell behavior.
Applicant Liberali Prisca
Number 183726
Funding scheme SNSF Professorships
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Cellular Biology, Cytology
Start/End 01.07.2019 - 30.06.2021
Approved amount 649'526.00
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All Disciplines (3)

Discipline
Cellular Biology, Cytology
Embryology, Developmental Biology
Genetics

Keywords (9)

Wnt signalling; Symmetry breaking mechanism; Pattern formation; Image-based screens; System Biology; Intestinal organoids; Environment sensing mechanism; Cell-to-cell variability; Single-cell approaches

Lay Summary (Italian)

Lead
“Collective behavior” o comportamento collettivo è un comportamento complesso nel quale l’analisi approfondita dei singoli elementi non necessariamente può spiegare il comportamento collettivo di molti singoli individui. Questo ricorda citazione di Aristotele: "Il tutto è più della somma delle sue parti". Il comportamento non spiegabile è l'auto-organizzazione del sistema. Spesso questa auto-organizzazione crea dei pattern (o schemi). Sulla terra, ad esempio, si formano le correnti oceaniche. In biologia molecolare e dello sviluppo, la formazione di pattern è un meccanismo attraverso il quale cellule inizialmente identiche in un tessuto assumono varie forme e funzioni nello spazio e nel tempo. Questo progetto estenderà il quadro teorico e sperimentale sviluppato nel progetto precedente per comprendere le proprietà collettive di cellule in una popolazione complessa e i pattern creati da singole cellule che interagiscono tra loro per formare un tessuto funzionale.
Lay summary

Per questo progetto useremo inizialmente un sistema modello di strutture intestinali in vitro chiamate organoid, che possono creare un tessuto intestinale funzionale da una singola cellula staminale intestinale. Studieremo il ruolo della Vitamina A e acido retinoico nello sviluppo intestinale e nella rigenerazione intestinale. Successivamente cercheremo i determinanti genetici di questa organizzazione con metodi genetici a singola cellula. Infine estenderemo le nostre tecnologie e i nostri concetti a un nuovo sistema modello in vitro che mimica lo sviluppo di tessuto neuronale.

Complessivamente, questo progetto di ricerca rivelerà meccanismi cellulari e genetici del comportamento collettivo di cellule staminali, che troverà applicazioni generali di là del sistema modello specifico del organoid intestinale e neuronali. Essa fornirà un esempio concreto di come un approccio quantitativo interdisciplinare, combinando diversi elementi sperimentali e teorici, consenta lo studio del comportamento collettivo che rimane, da molto tempo, uno degli aspetti fondamentali in biologia molecolare e dello sviluppo.

Direct link to Lay Summary Last update: 28.01.2019

Responsible applicant and co-applicants

Employees

Publications

Publication
Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis
Yang Qiutan, Xue Shi-Lei, Chan Chii Jou, Rempfler Markus, Vischi Dario, Gutierrez Francisca Mauer, Hiiragi Takashi, Hannezo Edouard, Liberali Prisca (2020), Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis, in BioRxiv, 1.
Engineering human knock-in organoids
Yang Qiutan, Oost Koen C., Liberali Prisca (2020), Engineering human knock-in organoids, in Nature Cell Biology, 261.
Exploring single cells in space and time during tissue development, homeostasis and regeneration
Mayr Urs, Serra Denise, Liberali Prisca (2019), Exploring single cells in space and time during tissue development, homeostasis and regeneration, in Development, 146.
From single cells to tissue self‐organization
(2019), From single cells to tissue self‐organization, in FEBS Journal, 1495.
Self-organization and symmetry breaking in intestinal organoid development
(2019), Self-organization and symmetry breaking in intestinal organoid development, in Nature, 66.

Collaboration

Group / person Country
Types of collaboration
Prof. Dana Pe'er, Colombia university, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Hugo Snippert Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Jan Skotheim United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
157531 An image-based systems biology approach to symmetry breaking in collective cell behavior 01.07.2015 SNSF Professorships

Abstract

A model system of intestinal organoid structures in vitro, which recapitulates most of the processes of morphogenesis and patterning observed in intestinal tissue, is used to understand self-organization and the symmetry-breaking events during collective cell behavior. The symmetry-breaking event can be observed when, despite all single cells in a growing organoid are exposed to a uniform growth-promoting environment, only a fraction of cells acquires specific cell fates, generating asymmetric structures such as crypts and villi. To understand this process in a quantitative and unbiased manner, we developed advanced single-cell imaging and image analysis of intestinal stem cells in 3D organoid development, as well as a novel approach for mapping genetic interactions. For this project prolongation, we will follow-up on our identified network of functional genetic interactions in organoid formation, by analyzing the role of a Retinoic Acid gradient, generated by enterocytes that act anti-parallel to the Wnt gradient generated by Paneth cells, to maintain the spatial organization of differentiated cells during tissue regeneration in intestinal crypts. We will then address the most challenging aspect of cell-to-cell variability: how to perturb it and study causal effects. In order to perturb different subpopulations of cells in intestinal organoid development with spatial and temporal resolution, we will first characterize cis-regulatory regions required for intestinal stem cell differentiation to then use them to specifically visualize and perturb subpopulations and cell-to-cell variability. Finally, we will explore new avenues by using the experimental and computational framework developed in the past three years in intestinal organoids to reveal the determinants of self-organization and symmetry breaking in neurogenesis with neuro-rosettes, neuro-cysts, and brain organoids. This project extension will consolidate the previous project and open new prospects on how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behavior resulting in the formation of complex multicellular asymmetric structures such as intestinal and brain organoids.
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