Heart Regeneration

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 (Rupert et al 2020 Plos One, Rupert et al 2020 Stem Cells Int).  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). With collaborators in the Srivastava lab at Brown, we developed a three-dimensional strain continuum predictive model to allow for micro-structural design optimization and analysis of effectiveness of the implanted patches (Bai et al 2021), and with collaborators in the Callanan lab at the University of Edinburgh, we are utilizing biomaterials beyond collagen in anisotropic scaffolds for applications in the heart and beyond (Reid et al 2021).

Developing Vasculature in Engineered Tissue

We are inducing the host heart to more efficiently vascularize implanted 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. This localized delivery of angiogenic factors from biomaterials within the implanted muscle tissue increased global heart function in ischemia/reperfusion injured rat hearts (Munarin et al 2020). We have also shown that patterned endothelial cell-lined vessels promote early chemotaxis from host vascular populations (Kant et al 2021). Heparin modification of alginate microspheres allows for controlled release of VEGF to improve vascularization (Munarin et al 2021) and or can be utilized with pleiotrophin (PTN), a heparin-binding factor with significant angiogenic activity (Rountree et al 2021).

Electrical Coupling of Implanted and Host Tissue