Embryonic stem cell‐derived cardiomyocytes as a model to study fetal arrhythmia related to maternal disease

Abstract

Embryonic stem cell-derived cardiomyocytes (ESC-CM) have many of the phenotypic properties of authentic cardiomyocytes, and great interest has been shown in their possibilities for modelling human disease. Obstetric cholestasis affects 1 in 200 pregnant women in the United Kingdom. It is characterized by raised serum bile acids and complicated by premature delivery and unexplained fetal death at late gestation. It has been suggested that the fetal death is caused by the enhanced arrhythmogenic effect of bile acids in the fetal heart, and shown that neonatal susceptibility to bile acid-induced arrhythmia is lost in the adult rat cardiomyocyte. However, the mechanisms of the observed bile acid effects are not fully understood and their in vivo study in human beings is difficult. Here we use ESC-CM from both human and mouse ESCs to test our proposal that immature cardiomyocytes are more susceptible to the effect of raised bile acids than mature ones. We show that early ESC-CM exhibit bile acid-induced disruption of rhythm, depression of contraction and desynchronization of cell coupling. In both species the ESC-CM become resistant to these arrhythmias as the cells mature, and this develops in line with the respective gestational periods of mouse and human. This represents the first demonstration of the use of ESC-CM as a model system for human cardiac pathology, and opens the way for both investigation of mechanisms and a high throughput screen for drug discovery.

Bile Acid Signaling in Fetal Tissues: Implications for Intrahepatic Cholestasis of Pregnancy

“…ESCM with a more immature (i.e. fetal-like) phenotype were more susceptible to developing a TC-induced abnormal rate, rhythm and amplitude of contraction, and desynchronization of calcium dynamics than cardiomyocytes with a more mature phenotype [22]. These data are consistent with the observation that mothers with ICP do not have arrhythmia.…”

Preconditioning and Stem Cell Survival

“…After the recent National Institutes of Health Policy changes regarding the use of embryonic stem cells, investigative efforts for their use in regenerative medicine have been intensified. Embryonic stem cells can provide a clinically relevant and renewable source of cardiomyocytes and endothelial cells for engraftment [2,118]. Despite their ability to adopt cardiac phenotype, their use is not without technical limitations of undifferentiated propagation in vitro and difficulty of purification of spontaneously differentiated cardiomyocytes from cell culture.…”

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

“…However, stem cell-derived cardiomyocytes can be matured through extended time in culture, and further maturation is being developed using such techniques as mechanical stretching, pharmacological or neurohormonal treatment, and chemical or conformational modulation of the growth substrate. Matured cells also seem to adopt a more adult phenotype in terms of arrhythmic propensity (Abdul Kadir et al, 2009).…”