Reconstructing the heart using iPSCs: Engineering strategies and applications

Abstract

Induced pluripotent stem cells (iPSCs) have emerged as a key component of cardiac tissue engineering, enabling studies of cardiovascular disease mechanisms, drug responses, and developmental processes in human 3D tissue models assembled from isogenic cells. Since the very first engineered heart tissues were introduced more than two decades ago, a wide array of iPSC-derived cardiac spheroids, organoids, and heart-on-a-chip models have been developed incorporating the latest available technologies and materials. In this review, we will first outline the fundamental biological building blocks required to form a functional unit of cardiac muscle, including iPSC-derived cells differentiated by soluble factors (e.g., small molecules), extracellular matrix scaffolds, and exogenous biophysical maturation cues. We will then summarize the different fabrication approaches and strategies employed to reconstruct the heart in vitro at varying scales and geometries. Finally, we will discuss how these platforms, with continued improvements in scalability and tissue maturity, can contribute to both basic cardiovascular research and clinical applications in the future.

Keywords: 3D bioprinting; Cardiac organoids; Cardiovascular tissue engineering; Engineered heart tissue; iPSC.

Fig. 1.

Cardiac tissue engineering using iPSCs. (A) The directed differentiation of patient-specific iPSCs into various cardiovascular lineages (e.g., iPSC-CMs, iPSC-ECs, iPSC-CFs, and iPSC-vSMCs) and the subsequent maturation of differentiated cells to near-adult states require coordinated signals derived from not only soluble (biochemical) factors, but also the material properties of surrounding ECM as well as exogenous biophysical stimuli. (B) While conventional culture methods rely solely on the addition of soluble factors on rigid 2D plastic, tissue engineering approaches bring together diverse devices, tools, and biomaterials to provide cells with the appropriate microenvironmental cues to generate physiological 3D tissue. (C) Example categories of cTE models reported in recent years, ranging from spheroids to chamber-forming engineered ventricles.

Fig. 2.

Applications of cardiac tissue engineering. Engineered human cardiac tissue derived from iPSCs offer unique opportunities for both basic and clinical research by bridging the gap between conventional 2D monolayers and animal models. Continued improvements in the scalability and physiological maturation of engineered cardiac tissues will enable: (i) complex disease modeling in a dish to unmask pathological phenotypes that are otherwise difficult to observe in 2D models, (ii) high-throughput systematic investigation of tissue-level responses to drugs and environmental pollutants/stressors, and (iii) novel cardiac regenerative therapies with improved cell retention and electromechanical integration.