Cardiac tissue engineering using human stem cell-derived cardiomyocytes for disease modeling and drug discovery

Abstract

Cardiovascular disease (CVD) is the most prevalent health problem in the world, and the high mortality rate associated with irreversibly injured heart muscle motivates an urgent need for the development of novel therapies to treat damaged myocardium. Recently, human engineered cardiac tissues (hECT) have been created using cardiomyocytes derived from human embryonic stem cells and human induced pluripotent stem cells. Although a healthy adult phenotype remains elusive, such hECT display structural and functional properties that recapitulate key aspects of natural human myocardium, including dose related responses to compounds with known chronotropic, inotropic and arrhythmogenic effects. Thus, hECT offer the advantage over traditional in vitro culture models of providing a biomimetic 3D environment for the study of myocardial physiopathology, and may be used to generate preclinical models for the development and screening of therapies for CVD.

Figure 1.. Paths toward the development of patient-specific in vitro 3D human engineered cardiac tissues (hECT) for in vitro disease modeling and drug discovery.

Allogeneic cells (light green), including human embryonic stem cells (hESC) and mesenchymal stem cells (hMSC), are excellent resources even though they are not patient-specific; hESC-derived cardiomyocytes (CMs) have been the main source for creating hECT to date. Adult cardiomyocytes from patients (red) are very limited in supply and are quiescent, thus requiring new culture optimization approaches to induce in vitro proliferation and obtain cell numbers sufficient for creating hECT. Autologous cell sources (pink) include bone marrow hMSCs and somatic cells reprogrammed into induced pluripotent stem cells (hiPSC), which can then be differentiated into cardiomyocytes. The hCMs thus obtained typically exhibit characteristics of the immature heart; therefore, conditioning processes (green) must be optimized to induce phenotypic maturation of engineered cardiac cells and tissues. The procedures and applications for which such hECT can be implemented are multifarious (blue), including a) characterization and functional assessment to investigate cardiac development and physio-pathological processes, b) modification of hECT as disease models for specific cardiac anomalies, and c) utilization of hECT to develop novel therapeutic approaches, and for drug screening and toxicology applications.