ORGANIZE · Origins of cell diversity in multicellular tissues
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-11-01 → 2023-10-31
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Origins of cell diversity in multicellular tissues
Multicellular tissues, and ultimately complex organisms, are composed of multiple distinct cell types that differ in function and phenotype. Such diversity in cell composition (i.e. phenotypic diversity) arises during development and tissue regeneration, where progenitor cells differentiate along multiple cell fate lineages to form a heterogeneous population. To ensure the proper form and function of the tissue, cell types must achieve the correct equilibrium in cell type proportions and self-organize into higher order structures. Indeed, loss or misregulation of phenotypic diversity can lead to a variety of diseases such as cancer and autoimmune disorders. While the molecular signals (i.e. cell states) that specify individual cell fates are widely studied in the context of development and stem cell engineering, less is known about how multiple cell types can simultaneously emerge from a seemingly homogeneous population and form a complex multicellular system with specified form and function. Though this multitude of cell states and types are present and heterogenous across the cell population, the cause and consequence of this diversity is poorly understood. There is a concomitant lack of tools to quantify cell heterogeneity in a multicellular system and measure its effect on emergence of tissue form and function. The aim of this project is to develop quantitative methods to measure single-cell heterogeneity in a 3D multicellular system and to investigate the role of this heterogeneity in emergence of shape complexity of the tissue. As a result, we developed a workflow for quantitative 3D image-based analysis of single-cell state as well as tissue-level morphology and use it to define measures of heterogeneity and complexity during the self-organization of a model 3D multicellular system, mouse small intestinal organoids. We are using this framework to generate a morphological landscape of organoids under varying growth conditions and correlate phenotypic diversity with emergence of morphological complexity. We also compare the predominantly cell-intrinsic self-organization of organoids to small intestinal development within the in vivo context of the organism. This project answers fundamental unresolved questions in developmental and systems biology on the role of cell diversity in multicellular tissues, how heterogeneous cell processes can ensure robust organization of a tissue, and the maintenance of phenotypic equilibrium in tissue homeostasis and disease.
Data: CORDIS, © European Union
Project objective
Multicellular tissues, and ultimately complex organisms, are composed of multiple distinct cell types that differ in functional attributes. Such diversity in cell composition (i.e. phenotypic diversity) arises during development and regeneration, where progenitor cells differentiate along multiple cell fate lineages to form a heterogeneous population. While the molecular signals (i.e. cell states) that specify individual cell fates are widely studied, less is known about how multiple cell types can simultaneously emerge from a seemingly homogeneous population and which molecular mechanisms coordinate this process on a tissue-wide scale. Increasing evidence suggests that stochastic events, as opposed to hard-wired deterministic processes, are critical for emergence of heterogeneity. However, the molecular mechanisms that drive stochasticity and diversity in a mammalian tissue remain unknown, mainly due to a scarcity of tools to measure stochastic events in large numbers of single cells and to perturb cell-to-cell heterogeneity on a tissue level. Here I propose to use quantitative single-cell imaging, transcriptomic approaches, and optogenetic control of tissue heterogeneity to identify the molecular mechanisms driving phenotypic diversity. I will apply these techniques to mouse intestinal organoids, a multicellular system that recapitulates the intestinal epithelium. I hypothesize that variability in cell state (at the single-cell level) drives cell phenotypic diversity (at the tissue level). Different combinations of dynamic molecular signals within single cells may thereby pattern populations within a tissue to adopt specific fate outcomes. Gaining insight into the mechanisms of phenotypic diversity will answer fundamental questions in developmental and synthetic biology on the origins of cell diversity in multicellular tissues, how stochastic processes can ensure developmental robustness, and the maintenance of phenotypic equilibrium in homeostasis and disease.
Original text from CORDIS.
Participants
- FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION · BASELCoordinatorSwitzerland
Links
Data: CORDIS, © European Union