Development of a novel technology to engineer heart muscle for contractile and paracrine support in heart failure

Abstract

The human heart has poor endogenous regeneration. If myocytes are lost due to injury, the myocardium is unable to restore its myocyte content and instead undergoes compensatory hypertrophy and remodeling. Cardiac tissue engineering aims to recreate and provide functional myocardium that replaces the injured myocardium. In this study, human engineered heart muscle (EHM) from cardiomyogenically differentiated human embryonic stem cells was generated. EHMs consisted of elongated, anisotropically organized cardiomyocyte bundles and responded “physiologically” to increasing calcium concentrations. To generate large myocardium capable of encompassing the ventricles, a novel process to systematically upscale the dimensions of engineered myocardium to a humanized Biological Ventricular Assisted Device (hBioVAD) was introduced. The hBioVADs formed a “pouch-like” myocardium at rabbit heart dimensions and were beating spontaneously. Further enhancement by biomimetic pulsatile loading generated “more mature” myocardium. Additional paracrine functionality was integrated by generating insulin-like growth factor-1 (IGF-1) secreting fibroblasts for tissue engineering applications. IGF-1 release induced higher levels of Akt phosphorylation and hypertrophy in cardiomyocytes resulting in increased force generation of EHM. Finally, feasibility of “paraBioVAD” (IGF-1 cell line and cardiomyocytes) implantation was demonstrated in a healthy rat model. Histological observations demonstrated engraftment on the heart and the presence of vascular structures. In conclusion, a humanized “paraBioVAD” technology for mechanic and paracrine heart support was developed. Future studies will assess its therapeutic utility in heart failure