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

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.

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

“…In this regard, the transcriptomic analysis comparing hiPSC-CMs 3D EHTs, 2D monolayers, and hCO with both human fetal and adult myocardial CMs determined hCO to be the best model in terms of recapitulating the transcriptome of the adult myocardium. Importantly, the results of this study indicate the enrichment of immune regulatory pathways in adult myocardium that is not recapitulated in in vitro CM models (observed to a minor extent in hCO) (151) (37,83,(87)(88)(89). This further emphasizes the need for immune cell incorporation in multicellular heart tissues as previously mentioned (151).…”

“…Importantly, the results of this study indicate the enrichment of immune regulatory pathways in adult myocardium that is not recapitulated in in vitro CM models (observed to a minor extent in hCO) (151) (37,83,(87)(88)(89). This further emphasizes the need for immune cell incorporation in multicellular heart tissues as previously mentioned (151). The impact of organoid models on CM maturation was recently shown by Silva et al (152); the authors generated hiPSCderived multilineage organoids [i.e., cardiac (mesoderm) and gut (endoderm)] with pronounced structural and functional maturation effects especially on atrial/nodal CMs.…”

Rotational Activity around an Obstacle in 2D Cardiac Tissue in Presence of Cellular Heterogeneity

“…However, the applications of mathematical methods in cardiac research are much more wide-ranging, for example, for the analysis of population studies [41]. Moreover, currently in vitro cardiac models from stem cells are of great interest [42,43]. Such a system can also be studied using corresponding mathematical models [44].…”

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

“…Cardiac organoids resemble the human heart by exhibiting similar ultrastructure and physiology, including oxidative metabolism, force-frequency relationship, and calcium handling [ 298 ]. Transcriptomic analysis revealed that cardiac organoids share the highest degree of similarity with human adult myocardium compared with 2D, 3D hiPSC-CMs, and fetal myocardium [ 331 ]. Small-size engineered heart tissue platforms have also been described [ 332 ].…”