Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies

Abstract

It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.

Cryopreservation of human pluripotent stem cell-derived cardiomyocytes is not detrimental to their molecular and functional properties

“…Advances in hPSC-CM generation and phenotyping have made them valuable as in vitro models for studying human heart development and cardiovascular disease, as well as for cardiac safety pharmacology, drug screening, and drug discovery (Brandão et al, 2017;Hartman et al, 2016;Magdy et al, 2018). While it is now possible to efficiently generate large quantities of relatively pure hPSC-CMs (Kempf and Zweigerdt, 2018), these procedures are timeconsuming, laborious, and are still subject to variability in reproducibility between successive differentiations (Burridge et al, 2015;Kempf et al, 2014).…”

“…Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are now an established in vitro model and tool for studying cardiovascular development and disease, safety pharmacology and drug development, as well as having potential therapeutic applications (Brandão et al, 2017;Hartman et al, 2016;Magdy et al, 2018). Due to the significant progress made in efficiently differentiating hPSCs to cardiomyocytes, it is now possible to generate the large quantities of hPSC-CMs required for these purposes which can then be evaluated using a multitude of assays (Denning et al, 2016).…”

“…To date there have been no reports comparing the in vitro phenotype and physiological properties of cryopreserved and non-frozen hPSC-CMs following replating. Such studies are warranted due to the increasing use of hPSC-CMs for investigating disease mechanisms and in safety pharmacology assays (Brandão et al, 2017;Denning et al, 2016;Giacomelli et al, 2017). For this reason, we have evaluated freshly-derived and cryopreserved cardiomyocytes generated from two different human induced pluripotent stem cell lines (hiPSC-CMs).…”

Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

“…The list of disease models used in the analysis is provided in Supplemental Table S1. This list was generated by initially examining referenced articles from multiple comprehensive reviews published in the field, [9][10][11][12][13][14] . The resulting publication list was then screened for additional relevant publications that were then examined manually.…”

Isogenic sets of hiPSC-CMs harboringKCNH2mutations capture location-related phenotypic differences

“…Cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) are now wellestablished as models for LQT2 [15][16][17][18] . Indeed, a number of hiPSC lines have been derived from both symptomatic and asymptomatic patients with mutations in various regions of hERG 19 . However, as these lines are from different individuals, they harbour additional genetic variants that may functionally influence the disease phenotype observed and limit the utility of hiPSC-derived cardiomyocytes (hiPSC-CMs) for broad intragenotype risk stratification.…”