This project seeks to understand how mechanical forces shape cardiac development, and to use this knowledge to engineer human cardiac tissues with improved electromechanical function. I will combine two novel platforms, a protein-based nanomechanical biosensor for mapping in vivo tissue strain, and an iPSC- derived 3-D engineered cardiac tissue environment to evaluate tissue contractility and electrophysiology during tissue formation. In developing cardiac muscle, mechanical forces are integral to a range of processes including cell differentiation, tissue morphogenesis, electrophysiology and contractility, but exact roles remain unknown. When mechanical forces are perturbed by experimental intervention or developmental abnormalities, their disruption can lead to congenital heart defects and disease. With advances in regenerative medicine and the use of induced pluripotent stem cell (iPSCs) for tissue engineering, new approaches for repairing damaged heart tissue have emerged. However, there has been limited success bringing engineered cardiac systems to the clinic, and we remain far from generating an engineered heart. This suggests that the field lacks thorough understanding of the mechanical forces driving functional and structural maturation of engineered cardiac tissue. Here I propose that knowledge of the magnitudes, developmental timing, and directionality of cellular strain in developing cardiac tissue in vivo can be used to improve the construction of iPSC-derived 3-D engineered cardiac tissues, leading to increased tissue contractility and clinical utility.
Aim 1 will elucidate the mechanical forces shaping cardiac tissue development via design, construction and experimental validation of a protein-based nanomechanical strain biosensor. Additionally, I will utilize this strain biosensor to map tissue strain throughout cardiac looping via in vivo and ex vivo Xenopus cardiac development models.
Aim 2 will determine the biomechanical strains sufficient to improve human iPSC-derived cardiac tissue contractility and electrophysiology. By mapping the biomechanics of cardiac tissue development from Aim 1 and integrating the observed forces into the iPSC-derived 3-D cardiac tissue engineering process, I will determine the consequences of recapitulating in vivo strain fields on tissue structure, gene expression and contractility. While this proposal seeks to enhance our knowledge of biomechanical forces during tissue formation and improve engineered cardiac tissue models, the tools created will have wide utility in understanding the complex role between biomechanical forces and tissue development. By the end of the project, I will have developed and validated these technologies using coupled in vitro and in vivo systems, along with obtaining expertise in biomechanical and tissue engineering. Long-term, the knowledge gained should improve the engineering of human cardiac tissues for applications in heart regeneration.
Cell-generated mechanical forces are essential for proper cardiac development, and disruption of these forces leads to developmental abnormalities and congenital defects, a leading cause of infant mortality. This proposal will measure these forces during cardiac development, in order to improve our understanding of heart formation, as well as provide potential strategies for utilizing applied forces to engineer new heart muscle from pluripotent stem cells. By using an innovative protein-based sensor to map mechanical strain in vivo during cardiac tissue development, we plan to utilize this data to improve the engineering of human cardiac tissues, and bring us one-step closer to understanding the principles of regeneration to treat cardiac disease.
