Multicellular Human Cardiac Organoids Transcriptomically Model Distinct Tissue-Level Features of Adult Myocardium.

Charles M Kerr,Ying Mei,Dylan Richards,Kristine Y Deleon-Pennell,Donald R Menick

doi:10.3390/ijms22168482

Abstract

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for disease modeling and drug cardiotoxicity screening. To this end, we recently developed human cardiac organoids (hCOs) for modeling human myocardium. Here, we perform a transcriptomic analysis of various in vitro hiPSC-CM platforms (2D iPSC-CM, 3D iPSC-CM and hCOs) to deduce the strengths and limitations of these in vitro models. We further compared iPSC-CM models to human myocardium samples. Our data show that the 3D in vitro environment of 3D hiPSC-CMs and hCOs stimulates the expression of genes associated with tissue formation. The hCOs demonstrated diverse physiologically relevant cellular functions compared to the hiPSC-CM only models. Including other cardiac cell types within hCOs led to more transcriptomic similarities to adult myocardium. hCOs lack matured cardiomyocytes and immune cells, which limits a complete replication of human adult myocardium. In conclusion, 3D hCOs are transcriptomically similar to myocardium, and future developments of engineered 3D cardiac models would benefit from diversifying cell populations, especially immune cells.

Highlights

Cardiovascular disease is the leading cause of death worldwide [1]
We recently demonstrated that our human cardiac organoids (hCOs) recapitulated tissue-level hallmarks of myocardial infarction and reproduced process-level transcriptomic shifts occurring in both human ischemic cardiomyopathy and a murine myocardial infarction [12]
We investigated the transcriptomes of in vitro human cardiovascular models (2D iPSC-CMs, 3D iPSC-CMs and hCOs) and compared them to publicly available bulk RNA-seq datasets of healthy human myocardium derived from fetal atria, fetal ventricles and adult ventricles

Summary

Introduction

Cardiovascular disease is the leading cause of death worldwide [1]. While interventional therapies have significantly reduced mortality in patients suffering from acute cardiovascular disease, the success of these therapies contributes to a higher prevalence of heart failure in an aging population [2,3]. Fewer novel cardiovascular therapies succeed through clinical trials [4], which has been attributed to low tolerance in drug toxicity [5], high research and development costs [6], and interspecies differences between animals and humans [7]. These challenges impeding cardiovascular drug development illustrate a growing need for effective in vitro models of human myocardium. The need for human myocardium models has prompted extensive applications of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in a twodimensional (2D) culture for cardiovascular drug and toxicity screening [8,9,10]. We aim to evaluate our hCO’s recapitulation of homeostatic human myocardium and characterize the biomimetic transcriptomic properties of 3D cardiac microtissues

Objectives

Methods

Results

Conclusion