ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes

Abstract

Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart. We observed that heart organoids in diabetic conditions develop pathophysiological hallmarks like those previously reported in mouse and human studies, including ROS-mediated stress and cardiomyocyte hypertrophy, among others. Single cell RNA-seq revealed cardiac cell type specific-dysfunction affecting epicardial and cardiomyocyte populations, and suggested alterations in endoplasmic reticulum function and very long chain fatty acid lipid metabolism. Confocal imaging and LC-MS lipidomics confirmed our observations and showed that dyslipidemia was mediated by fatty acid desaturase 2 (FADS2) mRNA decay dependent on IRE1-RIDD signaling. We also found that the effects of pregestational diabetes could be reversed to a significant extent using drug interventions targeting either IRE1 or restoring healthy lipid levels within organoids, opening the door to new preventative and therapeutic strategies in humans.

Maternal Pre-Existing Diabetes: A Non-Inherited Risk Factor for Congenital Cardiopathies

“…A recent study on human cardiac organoids showed that PGD induced ER stress and dysregulation of lipid metabolism. Treatment of ER stress reduced the deleterious effects associated with PGD in human cardiac organoids [129].…”

The new era of cardiovascular research: revolutionizing cardiovascular research with 3D models in a dish

“…Importantly, these organoids displayed robust beating and electrophysiological activity with well-defined action potential (AP) waves reminiscent of QRS complexes, T, and P waves detected by a multielectrode array (MEA) system. Additionally, this type of organoid was successfully used to model pregestational diabetes (PGD) -induced congenital heart defects, showing structural, metabolic, and functional changes in organoids under diabetic conditions [ 17 , 24 ]. Another recent study developed an “epicardioid” with an inner core of ventricular CMs and a thick envelope containing epicardial cells [ 25 ].…”

“…Owing to the rapid pace of advances in the development of cardiac organoids in recent years, other CHD syndromes like hypoplastic left heart syndrome (HLHS), Ebstein’s anomaly, and Noonan syndrome have also been successfully modeled using cardiac organoids [ 22 , 25 , 60 ]. Additionally, environmental factors such as PGD-induced CHD can also be mimicked in organoids under defined conditions [ 17 , 23 , 24 ]. As one of the most common non-genetic factors causing CHD, PGD results in a 12-fold increase in the occurrence of CHD, fetal hypertrophic cardiomyopathy, and impaired cardiac function in infants [ 61 , 62 ].…”

“…Aguirre’s group cultured cardiac organoids under PGD-like conditions (high insulin and glucose) and found that the organoids had decreased oxygen consumption, increased glycolysis, accumulation of lipid droplets, and an increased propensity for arrhythmias, suggesting altered glucose and lipid metabolism [ 17 , 23 ]. The same research group recently used this model to further elucidate the underlying mechanisms of PGD-induced CHDs [ 24 ]. Interestingly, they found that endoplasmic reticulum (ER) stress and very long chain fatty acid (VLCFA) lipid metabolism imbalance were two critical factors that gave rise to cardiac defects.…”

Biotechnological advances and applications of human pluripotent stem cell-derived heart models

“…Overall, the generation of human heart organoids based on cellular self-assembly shows promise in producing complex human heart tissues that require minimal maintenance and have high throughput ability. Such advanced organoids are suitable for addressing complex metabolic disorders associated with pathological conditions, such as congenital heart defects, including those induced by pregestational diabetes ( Lewis-Israeli et al, 2022 ; Kostina et al, 2023 ). In another study, we also produced self-assembled organoids with anterior-posterior patterning from an endogenous retinoic acid gradient originating at the atrial pole, where proepicardial and atrial populations reside, thereby mimicking the developmental process of the primitive heart tube ( Volmert et al, 2022 ).…”