Engineered human cardiac tissues for modeling heart diseases

Abstract

Heart disease is one of the major life-threatening diseases with high mortality and incidence worldwide. Several model systems, such as primary cells and animals, have been used to understand heart diseases and establish appropriate treatments. However, they have limitations in accuracy and reproducibility in recapitulating disease pathophysiology and evaluating drug responses. In recent years, three-dimensional (3D) cardiac tissue models produced using tissue engineering technology and human cells have outperformed conventional models. In particular, the integration of cell reprogramming techniques with bioengineering platforms (e.g., microfluidics, scaffolds, bioprinting, and biophysical stimuli) has facilitated the development of heart-ona- chip, cardiac spheroid/organoid, and engineered heart tissue (EHT) to recapitulate the structural and functional features of the native human heart. These cardiac models have improved heart disease modeling and toxicological evaluation. In this review, we summarize the cell types for the fabrication of cardiac tissue models, introduce diverse 3D human cardiac tissue models, and discuss the strategies to enhance their complexity and maturity. Finally, recent studies in the modeling of various heart diseases are reviewed. [BMB Reports 2023; 56(1): 32-42].

Fig. 1

Cell components and engineering platforms for the development of cardiac tissue models. Several types of cardiac tissue models have been developed, to include various cardiac cells, using engineering platforms such as microwells, microfluidic devices, functional hydrogel, and bioprinting. This figure was created with BioRender.com.

Fig. 2

Biophysical stimulation to improve the cardiac tissue models. (A) Cardiac spheroids cultured in microbioreactors and subjected to electrical stimulation at various frequencies. Electrical signals increased expression of gap junction and sarcomere thickness in cardiac spheroids. Adapted from Eng et al. (61) (CC BY 4.0 license) Copyright 2016, The Authors, published by Springer Nature. (B) EHT models stimulated with uniaxial cyclic stretch (10% strain, 1 Hz) using a bioreactor. The expression of gap junction and sarcomere structure and electrical responses were enhanced by mechanical stimulation. Adapted from Massai et al. (63) (CC BY 4.0 license) Copyright 2020, The Authors, published by Frontiers Editorial Office. (C) Ring-shaped EHT models with electrical pulses and stretch conditioning, which showed improved biomechanical properties and electrical coupling. Adapted from Lu et al. (64) (CC BY 4.0 license) Copyright 2021, The Authors, published by Ivyspring International Publisher.

Fig. 3

Modeling various heart diseases using cardiac tissue models. (A) Cardiomyopathy modeling using EHT with genetic defects of ACTN2. Adapted from Prondzynski et al. (74) (CC BY 4.0 license) Copyright 2019, The Authors, published by John Wiley and Sons. (B) Atrial arrhythmia modeling using ring-shaped EHT. Adapted from Goldfracht et al. (80) (CC BY 4.0 license) Copyright 2020, The Authors, published by Springer Nature. (C) Cardiac fibrosis modeling by assembling spheroids using 3D bioprinting. Adapted from Daly et al. (100) (CC BY 4.0 license) Copyright 2021, The Authors, published by Springer Nature.