In this project, we seek to define how extracellular matrix (ECM) components control the behavior of fetal cardiac cells in-vitro. With this knowledge, we seek to program custom-designed ECM mixtures that can induce programmable tissue-level behavior. Specifically, we want to replicate a key aspect of healthy heart development, myocardial trabeculation, and the defects seen in congenital heart disease (CHD).
Why did we decide to focus on CHD? Engineered tissue models are becoming increasingly important for society as they offer more predictive platforms for drug development. In fact, more predictive results than those obtained on traditional in-vitro and animal models were obtained when testing compounds on human cells grown on engineered substrates that mimic native microenvironments. Moreover, this approach is 3R complaint and promises to replace animal models entirely. At present, tho, no engineered platform focuses on CHD, a family of structural disorders that affect 1 in 100 European newborns.
Based on the PI previous work and existing literature in development biology, biophysics, and bioengineering, we hypothesized that three ECM components (agrin, hyaluronic acid, and laminin) and two cell types (fetal cardiomyocytes and endothelial cells) are responsible for myocardial trabeculation.
To test this hypothesis, we will follow a classical engineering bottom-up approach. First, we will develop a high-throughput platform to study ECM-cell interactions using live microscopy. We call it our TestBench and expect it to yield a library of well-characterized parts. Second, we will develop a computer-aided design tool to model ECM-cell interactions based on particle dynamics since we are specifically interested in modeling tissues that change during embryonic development and CHD. And third, we will leverage these well-characterized and computationally-modeled ECM-cell interactions to create designer-ECM that can program healthy and diseased myocardial trabeculation.
Importantly, we believe that the knowledge of the parts and their predicted interactions will help us precisely and mechanistically design engineered CHD in-vitro models, thus introducing new products (CHD in-vitro models) and a new process (programmable tissue models) in cardiac tissue engineering.
