Investigating the mechanobiology of multicellular morphogenesis - Project Summary The morphogenesis of multicellular systems has important implications in both development and diseases. Growing evidence suggests that mechanical signals present in the cellular microenvironment as well as the mechanical state of the cells play critical roles in morphogenetic processes, such as the branching dynamics in organ and gland development and invasive diseases like cancer, and the spatial organization and patterning of cells during these processes. Hence, understanding the mechanobiology of multicellular morphogenesis is of critical importance in both the fundamental biology of development and the treatment of human diseases via mechanomedicine or mechanical-based therapies. However, the complexity of the multicellular systems, especially in a three-dimensional physiologically relevant microenvironment, remains one of the biggest challenges in the field, largely due to a lack of appropriate quantitative tools. My laboratory has been building skills and developing new technologies to overcome this obstacle, including the engineering of in vitro and ex vivo multicellular cluster models and extracellular matrices with controlled physical properties, the development of computational mechanics approaches to quantify forces during branching morphogenesis, and the development of cell sorting platforms to characterize cellular mechanical phenotypes. In this MIRA application, we plan to apply and optimize these technologies to address some longstanding questions in the mechanobiology of morphogenesis. The goals for the next five years will be, first, to measure the distribution of intercellular mechanical forces during morphogenetic processes, including branch elongation/retraction, bifurcation/budding, and buckling, and connect these dynamic processes to mechanotransduction signaling and active cellular force generation. Second, we will engineer cell clusters of different sizes and shapes, and culture them in different extracellular environments. We will measure and model cellular bioenergetics to understand energy-driven morphogenesis. Third, we will sort cells based on their ability to generate contractile forces and use the sorted cell subpopulations to track and test if cells all actively adapt their mechanical phenotypes to a new environment or if only a subpopulation with a certain phenotype is selected by the new environment during development and disease progression. We will further screen and sequence the subpopulations to understand the genetic basis of the phenotypic difference in contractility. Together, this work will leverage the innovative tools we have been developing to address mechanobiology questions that were not possible previously, including how mechanical forces direct different branching dynamics, how cellular energy drives morphogenesis and cell patterning, and how heterogeneous mechanical phenotypes contribute to development and disease progression. The overall vision for this research program is for these new tools and new knowledge to help uncover novel therapeutic targets and lay the foundation for the future development of mechanomedicines.
