The capacity of multicellular systems to self-organize across biological scales, from molecules to cells to entire tissues and organisms that have specific functions and phenotypes, remains one of the most enigmatic processes in biology. Through complex networks of interactions and signaling feedback, cells differentiate along specialized lineages and organize to form larger-scale multicellular structures that themselves possess emergent, specialized properties within an organism. Though crucial for understanding multicellular development, homeostasis, and disease, such multicellular self-organization remains challenging to study as experimental and analysis methods must be suited to the study the large range of length scales and resolutions needed, from molecules, to cells, and to tissues. The approach of this project is to develop an analysis method that is able to bridge the biological scale between cells and tissues, where the 3D shape and structural properties of the multicellular system, e.g. the small intestinal organoid, is quantified along with its single-cell composition and molecular expression patterns at the cellular scale. This novel approach opens new questions and opportunities to analyze the origins of biological organization, patterning, and morphogenesis in 3D. In summary, the results of this project address a need for quantitative methods that bridge biological scales, uncovers a new role for cell heterogeneity during multicellular self-organization, and enables future mechanistic insights into emergence of tissue form and function from single cells within diverse multicellular systems.
