Deploying mechanosensitive cell-cell signaling to control in situ cardiovascular regeneration

Objective

Regenerative medicine aims to cure diseased tissues by restoring their physiological organization and thus functionality. In the context of in situ cardiovascular tissue engineering (CVTE), implanted biodegradable scaffolds gradually transform into living tissues, such as blood vessels and heart valves, via inflammation-driven neo-tissue growth and remodeling (G&R). Previous trial-and-error attempts to re-establish the physiological organization have mainly resulted in unexpected outcomes and high failure rates. Mechanistic computational models are urgently needed to unravel mechanisms and force breakthroughs in the field. Current computational models mainly focus on (sub)cellular G&R phenomena. Cell-cell signaling pathways that are critical for orchestrating tissue organization, and the key role of inflammatory cells in in situ regeneration have been largely ignored. In this project, I aim to develop novel computational models to understand how mechanosensitive Notch signaling in macrophages controls in situ cardiovascular regeneration. I will adopt a unique, multidisciplinary approach, where quantitative in vitro experiments will inform the development of multiscale computational models of Notch-mediated in situ regeneration. I will leverage these models to investigate how Notch-mediated G&R can be locally controlled via mechanical metamaterial scaffolds, to initiate the emergence of physiological tissue DESIGN. If successful, these mechanistic computational models will provide a new angle to understanding mechano-regulated G&R. They can give unprecedented insights into the underlying mechanisms of in situ regeneration, and can uncover novel strategies to regenerate physiologically organized tissues. This will not only push the frontiers of in situ CVTE, but also provide new outlooks for the broader field of regenerative medicine and for investigating pathologies in which inflammatory cells play a dominant role (e.g., atherosclerosis, myocardial infarction).