Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering

Abstract

Until recently, in vivo and ex vivo experiments were the only means to determine factors and pathways involved in disease pathophysiology. After the generation of characterized human embryonic stem cell lines, human diseases could readily be studied in an extensively controllable setting. The introduction of human-induced pluripotent stem cells, a decade ago, allowed the investigation of hereditary diseases in vitro. In the field of cardiology, diseases linked to known genes have successfully been studied, revealing novel disease mechanisms. The direct effects of various mutations leading to hypertrophic cardiomyopathy, dilated cardiomyopathy, arrythmogenic cardiomyopathy, or left ventricular noncompaction cardiomyopathy are discovered as a result of in vitro disease modeling. Researchers are currently applying more advanced techniques to unravel more complex phenotypes, resulting in state-of-the-art models that better mimic in vivo physiology. The continued improvement of tissue engineering techniques and new insights into epigenetics resulted in more reliable and feasible platforms for disease modeling and the development of novel therapeutic strategies. The introduction of CRISPR-Cas9 gene editing granted the ability to model diseases in vitro independent of induced pluripotent stem cells. In addition to highlighting recent developments in the field of human in vitro cardiomyopathy modeling, this review also aims to emphasize limitations that remain to be addressed; including residual somatic epigenetic signatures induced pluripotent stem cells, and modeling diseases with unknown genetic causes. Stem Cells Translational Medicine 2019;8:66-74.

Keywords: Cardiac disease; Heart failure; In vitro disease models; Stem cells.

Figure 1

Schematic representation of cell types as a basis for human in vitro models. Primary cells, cell lines and stem cells can be utilized as a basis for in vitro disease models to study cardiomyopathies. State‐of‐the‐art gene editing techniques allow for the introduction of specific disease‐causing mutations. Alternatively, gene editing can also be harnessed to generate isogenic control lines from patient‐derived cells.

Figure 2

Summary of different technical approaches to cardiac tissue engineering. Cardiac tissues can be generated by allowing cardiac cells to spontaneously form a tissue by self‐assembly. Other approaches include the introduction of a decellularized matrix as a basis for reconstituted cardiac tissue, injecting human cardiac precursor cells into the murine kidney and machine‐guided generation of cardiac tissue on a chip.