Designer extracellular matrices to program healthy and diseased cardiac morphogenesis

Title Designer extracellular matrices to program healthy and diseased cardiac morphogenesis
Start date 2020-10-01
End date 2025-09-30
Sponsor European Research Council - Starting Grant (ERC-StG)
Institution None

Associated cell lines

Project Description

To meet medical needs worldwide, tissue engineering must move from successful pre/clinical products towards an effective process, but progress is made difficult by the multiscale complexity of tissue biology. Historically, genetic engineers faced similar challenges: in a 2005 letter to Nature, Dr. Endy asked: “Despite tremendous individual successes […], why is the engineering of useful synthetic biological systems still an expensive, unreliable and ad hoc research process?”. The solution they found, synthetic biology (SYNBIO), leverages well-characterized DNA parts assembled into designer-DNA that trigger computationally predictable cellular behaviors. Effectively, SYNBIO introduced computer-aided design and manufacturing (CAD/M) to cellular engineering. Here, we want to extend that design framework to tissues using extracellular matrix (ECM) parts. We will leverage my experience with computational and experimental models in cardiac tissue engineering to establish well-characterized ECM parts and computational tools to create designer-ECM that predictably trigger tissue-level behaviors. To develop a CAD/M tool for engineering tissues, we will characterize ECM-induced changes in the gene expression (fluorescent in-situ sequencing), structure (fluorescently tagged cytoskeletal proteins), and function (traction force microscopy) of human induced pluripotent stem cell-derived cardiomyocytes and endothelial cells. We will then model these multiscale ECM-cell interactions by coupling ordinary differential equations and coarse-grain particle dynamics. Finally, we will leverage this CAD/M tool to bioprint designer-ECM that recapitulate myocardial morphogenesis: the process by which the muscular tissue of the heart builds itself during embryonic development. With SYNBIO.ECM, we will develop a novel CAD/M-based process for cardiac tissue engineering and introduce novel engineered tissue products: designer-ECM programmed to recapitulate heart development.