Periodic Reporting for period 4 - CoEvolve (Deconstructing and rebuilding the evolution of cell and tissue mechanoadaptation)
Reporting period: 2024-07-01 to 2024-12-31
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 project aimed 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 developed 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 dissected 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. At the single-cell level, we found intriguing evidence that cell phenotype and behavior are sensitively shaped by the spatial, geometrical, and topographical properties of the microenvironment. At the tissue level, we found that the formation and remodeling of tissues and organoids are modulated by the interactions between cells and the environment. This provides a unique handle to dynamically control cell functions through manipulations of the cell microenvironment.
These findings 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 developed 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 dissected 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. At the single-cell level, we found intriguing evidence that cell phenotype and behavior are sensitively shaped by the spatial, geometrical, and topographical properties of the microenvironment. At the tissue level, we found that the formation and remodeling of tissues and organoids are modulated by the interactions between cells and the environment. This provides a unique handle to dynamically control cell functions through manipulations of the cell microenvironment.
These findings 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.
Using these developed tools, we studied the role of dynamic cell-matrix interactions in cell and tissue functions, focusing on a few physiologically relevant phenomena. First, we demonstrated that the phenotype transition of fibroblasts – a cell type critical in wound healing, tissue maintenance, and homeostasis – is modulated by spatial organization of ligands in the substrate as well as the dynamic changes in the substrate geometry. This occurs through a mechanoadaptation mechanism that is mediated by the cells’ adhesion, cytoskeletal rearrangement, and nucleus localization. Furthermore, we showed that the interplay between cell-cell and cell-matrix interactions is important for cell’s mechanosensitivity to external cues such as dynamic strain, topography, and constraints. By manipulating these physical cues, it is possible to influence cell differentiation, organization, and even tissue formation.
These developments and findings have been reported in several peer-reviewed journal publications and presented in international conferences and meetings. We are currently pursuing this research direction further and are planning to apply for additional funding to extend the work.
Using these developed tools, we studied the role of dynamic cell-matrix interactions in cell and tissue functions, focusing on a few physiologically relevant phenomena. First, we demonstrated that the phenotype transition of fibroblasts – a cell type critical in wound healing, tissue maintenance, and homeostasis – is modulated by spatial organization of ligands in the substrate as well as the dynamic changes in the substrate geometry. This occurs through a mechanoadaptation mechanism that is mediated by the cells’ adhesion, cytoskeletal rearrangement, and nucleus localization. Furthermore, we showed that the interplay between cell-cell and cell-matrix interactions is important for cell’s mechanosensitivity to external cues such as dynamic strain, topography, and constraints. By manipulating these physical cues, it is possible to influence cell differentiation, organization, and even tissue formation.
These developments and findings have been reported in several peer-reviewed journal publications and presented in international conferences and meetings. We are currently pursuing this research direction further and are planning to apply for additional funding to extend the work.
N/A, this is the final reporting period.