Tissue engineering the cardiac microenvironment: Multicellular microphysiological systems for drug screening

Abstract

The ability to accurately detect cardiotoxicity has become increasingly important in the development of new drugs. Since the advent of human pluripotent stem cell-derived cardiomyocytes, researchers have explored their use in creating an in vitro drug screening platform. Recently, there has been increasing interest in creating 3D microphysiological models of the heart as a tool to detect cardiotoxic compounds. By recapitulating the complex microenvironment that exists in the native heart, cardiac microphysiological systems have the potential to provide a more accurate pharmacological response compared to current standards in preclinical drug screening. This review aims to provide an overview on the progress made in creating advanced models of the human heart, including the significance and contributions of the various cellular and extracellular components to cardiac function.

Keywords: 3D tissue; Cardiotoxicity; In vitro drug screening; Stem cell-derived cardiomyocyte.

Fig. 1

The cardiac microenvironment. Microphysiological models of the heart have focused mostly on recapitulating the structures within the myocardium. Within a single section of the myocardium (approximately 100 μm), several important cell types are present (cardiomyocytes, endothelial cells, fibroblasts) in a specific structural arrangement to actively modulate the microenvironment.

Fig. 2

Three-dimensional cardiac tissue derived from hPSC-CM. (A) Embedding cardiomyocytes in 3D scaffolds result in disorganized structures, as the cardiomyocytes show random sarcomere orientation within the tissue (red = α-sarcomeric actin, blue = DAPI). (B) Using Velcro as an anchor along the edges, the 3D cardiac tissue displays mesoscopic organization and alignment (red = myosin heavy chain, green = sarcomeric α-actinin, blue = DAPI). Adapted and reprinted from [51] and [59] with permission from Elsevier.

Fig. 3

The influence of non-cardiomyocytes and other factors present in the native cardiac microenvironment. Using various modes of communication, cardiomyocyte functions are strongly affected by the presence of endothelial cells, fibroblasts, and other cells and secreted factors. Many of the responses that the cardiomyocytes undergo in the presence of these signals are closely tied to parameters that are commonly used as readouts for detecting cardiotoxicity, highlighting the significance of a complex microphysiological model for capturing a more physiological response to drugs.