Abstract
The knowledge acquired throughout the years concerning the in vivo regulation of cardiac development has promoted the establishment of directed differentiation protocols to obtain cardiomyocytes (CMs) and other cardiac cells from human pluripotent stem cells (hPSCs), which play a crucial role in the function and homeostasis of the heart. Among other developments in the field, the transition from homogeneous cultures of CMs to more complex multicellular cardiac microtissues (MTs) has increased the potential of these models for studying cardiac disorders in vitro and for clinically relevant applications such as drug screening and cardiotoxicity tests. This review addresses the state of the art of the generation of different cardiac cells from hPSCs and the impact of transitioning CM differentiation from 2D culture to a 3D environment. Additionally, current methods that may be employed to generate 3D cardiac MTs are reviewed and, finally, the adoption of these models for in vitro applications and their adaptation to medium- to high-throughput screening settings are also highlighted.
Highlights
The adult heart is a four-chamber organ, comprising the left and right atria, and the left and right ventricles, that is delimited by a heart wall composed of three different cell layers, the myocardium, the epicardium and the endocardium
Cardiotoxicity is an important focus of attention during models for cardiotoxicity screening assays and for modeling and studying cardiac disorders. In this the pre-clinical stage of the pipeline for the development of new drugs, the lack of more reliable and review, we present the state of the art of the methods for generating different cardiac cells from human pluripotent stem cells (hPSCs) predictive models compromises the accuracy of toxicity detection
They observed that upon embryoid body (EB) differentiation, hPSCs that had been previously cultured in micropatterned platforms (300 × 300 μm) showed an upregulation of the canonical Wnt signaling pathway during the first few days of differentiation when compared with 2D cultured hPSCs, which resulted in a higher expression of genes associated with primitive streak, mesoderm and cardiac lineage commitment
Summary
The adult heart is a four-chamber organ, comprising the left and right atria, and the left and right ventricles, that is delimited by a heart wall composed of three different cell layers, the myocardium, the epicardium and the endocardium. Bioengineering 2020, 7, x; doi: FOR PEER REVIEW in vitro, including long-term culture, electric stimulation, mechanic www.mdpi.com/journal/bioengineering load, culture with biomaterials, metabolic maturation and co-culture with other cardiac cells (reviewed in [5,6]) Among these strategies, the development of complex in vitro 3D cardiac models, recreating the cardiac cell heterogeneity and the 3D environment present in the human heart, has been deeply explored in the past few years, resulting in a remarkable improvement in hPSC-CMs maturity as well as in the overall cardiac tissue function. The development of complex in vitro 3D cardiac models, recreating the cardiac cell heterogeneity and the 3D environment present in the human heart, has been deeply explored in the past few years, resulting in a remarkable improvement in hPSC-CMs maturity as well as in the overall cardiac tissue function These results have boosted the potential of these cardiac in vitro models for cardiotoxicity screening assays and for modeling and studying cardiac disorders. We summarize some of the main lessons learned from the in vivo heart development process that have been applied to develop in vitro cardiac differentiation protocols from hPSCs
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