Tissue engineering, the controlled construction of tissues - cells and their extracellular matrix (ECM) environment - is a promising avenue of future biomedical applications. To realize this possibility, the dynamic and mutually interdependent relationship between cells and ECM has to be understood. The long-term goal of our research is to understand the interplay between cell and tissue dynamics during embryonic morphogenesis. In particular, the early avian embryo is an anatomically and experimentally tractable warm-blooded model organism, exhibiting a morphogenic sequence comparable in complexity to that of human embryos. The objective of this grant application is to provide a comprehensive and predictive computational model of the caudal avian embryo during the first day of development. The model will explain how tissue movements arise from the collective action of its constituent cells. Our central hypothesis is that the body plan of early amniote embryos is not established by "conventional" cell motility -- i.e., cells migrating on a rigid substrate to pre-defined positins following environmental cues. Instead, germ layers and the entire embryo morphology are molded to a large extent by cell- exerted mechanical forces (stresses) and their controlled dissipation/relaxation as well as cells moving by gaining traction from adjacent cells, cellular activities dubbed as "nonconventional motility" in this application. We propose a synergistic approach combining advanced imaging, molecular and mechanical perturbations, micro-rheology measurements, and computational modeling. Specifically, we propose to i) determine the contributions of "conventional" vs. "non-conventional" cell motility in the morphogenetic processes of early avian embryos, ii) identify the mechanical basis of "non- conventional" cell motility in early avian embryos, and iii) develop computational models to derive tissue-level growth laws from cellular activities. The empirical data generated during the proposed research will fill a gap in our knowledge of how most embryonic cells and the surrounding ECM moves during early development, and what are the corresponding spatio-temporal dynamics of mechanical stress within the tissues. The data will clarify the mechanism of a prevalent yet understudied mode of collective cell motility. Our efforts will create the first model that explain complex movements of a millimeter-sized piece of living material by resolving and relating events both at the tissue and individual cell level. Advanced optical microscopy and image analysis methods, as well as the resulting computational tools will enable future studies of more differentiated and functional tissues and increase our understanding of the tissue mechanics underlying physiological and pathological processes: such as bone and cartilage remodeling, wound healing or malignant cell invasion.
The project will help to establish a causal link between cell and ECM dynamics and the resulting tissue- scale behavior by a synergy of imaging, micro-rheology and computational modeling. The insights gained through the study of avian embryos will directly illuminate the biomechanics of normal development as well as of birth defects.
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