Sphingosine 1‐Phosphate receptor 1 (S1P
1
, encoded by
S1pr1
) is a G protein‐coupled receptor that signals in multiple cell types including endothelial cells and cardiomyocytes. Cardiomyocyte‐specific deletion of
S1pr1
during mouse development leads to ventricular noncompaction, with 44% of mutant mice surviving to adulthood. Adult survivors of embryonic cardiomyocyte
S1pr1
deletion showed cardiac hypertrabeculation consistent with ventricular noncompaction. Surprisingly, systolic function in mutant mice was preserved through at least 1 year of age. Cardiac conduction was abnormal in cardiomyocyte
S1pr1
mutant mice, with prolonged QRS intervals in mutants as compared with littermate control mice. Immunostaining of hearts from
S1pr1
mutant embryos displayed a zone of intermediate Connexin 40 (Cx40) expression in the trabecular myocardium. However, we observed no significant differences in Cx40 and Connexin 43 immunostaining in hearts from adult survivors of embryonic cardiomyocyte
S1pr1
deletion, which suggests normalized development of the ventricular conduction system in mutant mice. By contrast, the adult survivors of embryonic cardiomyocyte
S1pr1
deletion showed increased cardiac fibrosis as compared with littermate controls. These results demonstrate that ventricular hypertrabeculation caused by embryonic deletion of cardiomyocyte
S1pr1
correlates with cardiac fibrosis, which contributes to abnormal ventricular conduction. These results also reveal conduction abnormalities in the setting of hypertrabeculation with normal systolic function, which may be of clinical relevance in humans with ventricular hypertrabeculation.
IntroductionCongenital heart disease is the leading cause of death related to birth defects and affects 1 out of every 100 live births. Induced pluripotent stem cell technology has allowed for patient-derived cardiomyocytes to be studied in vitro. An approach to bioengineer these cells into a physiologically accurate cardiac tissue model is needed in order to study the disease and evaluate potential treatment strategies.MethodsTo accomplish this, we have developed a protocol to 3D-bioprint cardiac tissue constructs comprised of patient-derived cardiomyocytes within a hydrogel bioink based on laminin-521.ResultsCardiomyocytes remained viable and demonstrated appropriate phenotype and function including spontaneous contraction. Contraction remained consistent during 30 days of culture based on displacement measurements. Furthermore, tissue constructs demonstrated progressive maturation based on sarcomere structure and gene expression analysis. Gene expression analysis also revealed enhanced maturation in 3D constructs compared to 2D cell culture.DiscussionThis combination of patient-derived cardiomyocytes and 3D-bioprinting represents a promising platform for studying congenital heart disease and evaluating individualized treatment strategies.
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