Table 2 |.

Systems analyses and insights into the biology of hPSC-CMs

Level	Key findings to date	Future questions
Genome	Genetic variations influence hPSC phenotypes	What is the contribution of genetic variation to cardiomyocyte maturation in hPSC applications?
Epigenome	Dynamic changes in histone modifications and DNA methylation across development and identification of regulation of maturation by panels of microRNAs	How does the epigenetic state contribute to the maturity and/or immaturity of hPSC-CMs?
Transcriptome	Embryonic-like state of hPSC-CMs and identification of dysregulated genes in immature hPSC-CMs	Do changes at the RNA level reflect differences in protein expression and/or cell function? What limits maturation in vitro? Are differentially expressed genes necessary and sufficient for maturation?
Proteome	Fetal-like state of hPSC-CM	How do the various maturation approaches influence expressed proteins and post-translational states?
Metabolome	Identification of lipid biomarkers and flux of carbon sources, and discovering how the carbon source contributes to ATP production and nucleotide biosynthesis	How do metabolites influence the functional state of hPSC-CMs (such as contractility and electrophysiology)?
Environment	Contributions of substrate, co-culture with other cell types and cell density to maturation; role of integrin and microRNA signalling	How do interactions between cells and/or 3D cues mediate maturation? What are the key paracrine or other environmental factors?
Organ	hPSC-CMs induce remuscularization of infarcted myocardium and restoration of function after infarct but engrafted cells are arrhythmogenic	How can we balance efficacy and benefits with risks of the immature state of hPSC-CMs for cell therapy? What is the optimal maturity phenotype for cell-replacement strategies?

hPSC-CM, human pluripotent stem cell-derived cardiomyocyte.