Generation of human vascularized and chambered cardiac organoids for cardiac disease modelling and drug evaluation

TL;DR

Researchers created vascularized and chambered heart-like organoids to study heart diseases and test drugs more effectively.

Contribution

A three-step method to generate reproducible, vascularized, and chambered cardiac organoids for disease modeling and drug evaluation.

Findings

The organoids, called vaschamcardioids, showed 90% spontaneous beating and included six cell types.

Captopril reduced fibrosis and functional disorders in injury models, while doxorubicin caused dose-dependent toxicity.

The method enables robust modeling of cardiac injury and drug screening in a human-like system.

Abstract

Human induced pluripotent stem cell (hiPSC)‐derived cardiac organoids (COs) have shown great potential in modelling human heart development and cardiovascular diseases, a leading cause of global death. However, several limitations such as low reproducibility, limited vascularization and difficulty in formation of cardiac chamber were yet to be overcome. We established a new method for robust generation of COs, via combination of methodologies of hiPSC‐derived vascular spheres and directly differentiated cardiomyocytes from hiPSCs, and investigated the potential application of human COs in cardiac injury modelling and drug evaluation. The human COs we built displayed a vascularized and chamber‐like structure, and hence were named vaschamcardioids (vcCOs). These vcCOs exhibited approximately 90% spontaneous beating ratio. Single‐cell transcriptomics identified a total of six cell types in the vcCOs, including cardiomyocytes, cardiac precursor cells, endothelial cells, fibroblasts, etc. We successfully recaptured the processes of cardiac injury and fibrosis in vivo on vcCOs, and showed that the FDA‐approved medication captopril significantly attenuated cardiac injury‐induced fibrosis and functional disorders. In addition, the human vcCOs exhibited an obvious drug toxicity reaction to doxorubicin in a dose‐dependent manner. We developed a three‐step method for robust generation of chamber‐like and vascularized complex vcCOs, and our data suggested that vcCOs might become a useful model for understanding pathophysiological mechanisms of cardiovascular diseases, developing intervention strategies and screening drugs.

Hu and colleagues developed a three‐step method for robust generation of chamber‐like and vascularized cardiac organoids, and demonstrated their potentials in cardiac disease modelling and drug screening.

Figures