Periodic Reporting for period 2 - CoEvolve (Deconstructing and rebuilding the evolution of cell and tissue mechanoadaptation)
Período documentado: 2021-07-01 hasta 2022-12-31
Cells in our body are exceptionally robust: they constantly adapt their properties and behavior to their physical environment. Less appreciated but equally important, the extracellular matrix (ECM) around the cells also adapts to accommodate cell activity. This highly dynamic feedback between the cell and the ECM has been increasingly recognized to play a key role in not only tissue morphogenesis and functions, but also a variety of diseases, from cardiomyopathies to cancer. Moreover, it presents an unprecedented challenge in healthcare and therapeutics, especially regenerative medicine, as progress in this field requires a paradigm shift from conventional, static cell descriptions to a co-evolving cell and tissue physiology. This proposal aims to instigate this transformation by unravelling the fundamental biophysical principles behind cell–matrix dynamic reciprocity and generating a multiscale roadmap of mechanoadaptation critical in functional tissue regeneration.
To achieve this goal, we will develop cutting-edge in vitro manipulation tools to deconstruct and rebuild the dynamics of cells and the ECM independently and interactively, thereby granting us full spatiotemporal control of each component in the system. Using this unique tissue-environment-inspired bottom-up approach, we will dissect how 1) physical changes in the environment are sensed and elicit response by the cell, 2) cell-induced ECM remodeling contributes to mechanical signal transmission, and 3) these local changes are orchestrated into global coordinated mechanoadaptation at the tissue level. The findings will have a broad impact on our fundamental understanding of cell and tissue physiology by identifying novel concepts in mechanoadaptation and will offer specific biomaterial design principles for tissue regeneration. The developed methodology will also advance the field in new directions by enabling further studies on downstream cell and tissue (mal)functions under dynamic conditions.
To achieve this goal, we will develop cutting-edge in vitro manipulation tools to deconstruct and rebuild the dynamics of cells and the ECM independently and interactively, thereby granting us full spatiotemporal control of each component in the system. Using this unique tissue-environment-inspired bottom-up approach, we will dissect how 1) physical changes in the environment are sensed and elicit response by the cell, 2) cell-induced ECM remodeling contributes to mechanical signal transmission, and 3) these local changes are orchestrated into global coordinated mechanoadaptation at the tissue level. The findings will have a broad impact on our fundamental understanding of cell and tissue physiology by identifying novel concepts in mechanoadaptation and will offer specific biomaterial design principles for tissue regeneration. The developed methodology will also advance the field in new directions by enabling further studies on downstream cell and tissue (mal)functions under dynamic conditions.
In order to systematically dissect the dynamic biophysical interactions between cells and the matrix, it is necessary to develop experimental platforms where each of the components in the system can be independently and spatiotemporally manipulated. This has been the focus of our work, and we specifically address this at different levels of complexity. We have developed and characterized platforms that allows (1) microscale manipulation of the spatial location of ligands in the cell substrate, (2) on-demand manipulation of the non-planar structure of cell substrates, and (3) longitudinal manipulation of tissue and organoid formation. In addition, we have also developed analytical tools that will be used to analyze cell and tissue functionalities in these constructs.
With these tools, we have demonstrated that the dimensionality and mechanical support offered by the extracellular matrix can strongly influence cell activity, differentiation, and maturation. Furthermore, spatiotemporal manipulation of the cell-matrix interactions can directly affect cellular activity and dynamics, which translate to downstream cell phenotype and differentiation, and we are tracing these back to their sensory mechanisms of the microenvironment. Moreover, we also showed that this approach leads to functional tissues and organoids and is amenable for disease modeling as well as longitudinal manipulation and inhibition study. We will study these phenomena further, by establishing the link between the microscale mechanical signal transmissions within and between cells in the matrix to the macroscale reciprocity and cooperativity in the larger, mechanically active constructs.