Re-engineering Contractility of the Heart
The Coulombe Lab has funding to support multiple projects focused on regenerating the muscular wall of the heart and understanding cardiotoxicity. These projects have basic science and translational components, working across the continuum from molecules and cells to tissue and the whole heart.
KEYWORDS: regenerative medicine - cardiac tissue engineering - human induced pluripotent stem cells - cardiac cell biology - mechanics - biomaterials - revascularization - extracellular matrix - myocardial infarction
Engineering Mature, Contractile Cardiac Tissue
Using human induced pluripotent stem cells (hiPSCs) to derive cardiomyocytes, we form engineered cardiac tissue (ECT) and stimulate them mechanically, electrically, and biochemically to promote cardiomyocyte maturation in vitro. A combination of approaches enables targeting unique cellular processes to induce maturation. Biochemical stimulation with insulin-like growth factor-1 (IGF1) and neuregulin-1 (NRG1) induces cardiomyocyte proliferation and promotes maturation of metabolic pathways and contractility to enable a positive force-frequency response (Rupert et al. 2017 Stem Cells Int.). Purification of cardiomyocytes, co-culture of cardiomyocytes with other cardiac cell types, and understanding the non-myocyte hiPSC-derived population alters excitation-contraction coupling and the biophysics of contraction. Embedding of wet-spun collagen microfibers in a defined, anisotropic architecture aligns myofilaments and sarcomeres in ECTs (Kaiser et al. 2019 ACS Biomater Sci Eng).
Developing Vasculature in Engineered Tissue
We are inducing the host heart to more efficiently vascularize implaned human cardiac tissue using embedded alginate microspheres to deliver angiogenic growth factors. Microspheres release VEGF-A, FGF-2, and sonic hedgehog into the local microenvironment after implantation on ischemia/reperfusion injured rat hearts. Vascular perfusion enables detection of patent and efficiently perfused vessels originating from the host.
Electrical Integration of Engineered Tissue
Large, aligned engineered human cardiac tissue does not readily couple to pass electrical signals between host and graft when surgically implanted on the epicardial surface of injured hearts. Therefore, we are developing biological sutures in collaboration with Dr. Glenn Gaudette (WPI) and other methods to rapidly provide connection to pass the electrical signal. We use optical mapping of voltage and calcium transients in collaboration with Dr. Bum-Rak Choi (RI Hospital) to assess electrical patterns and arrhythmia risk.
Arrhythmogenesis of Environmental Toxicants
Utilizing a human iPSC-cardiomyocyte 3D microtissue platform, we assess dose sensitivity of environmental toxicants and pharmaceuticals for arrhythmic events by evaluating voltage and calcium handling via optical mapping in collaboration with Drs. Bum-Rak Choi and Ulrike Mende (RI Hospital).