Researchers used an advanced human heart organoid system to discover therapeutic compounds that may be contributing factors to this condition.
Researchers at Michigan State University have created an advanced human heart organoid system that models features of pregestational diabetes-induced congenital heart disease found in mice and humans. The results demonstrated that endoplasmic reticulum (ER) stress and lipid imbalance are important factors contributing to this disease, and that omega-3 exposure may be helpful.
The most common type of birth defect in humans is congenital heart disease. Pregestational diabetes, which affects mothers before and during early pregnancy, is an important cause of congenital heart disease, and the number of women with diabetes in their reproductive years is on the rise. A newborn born to a mother with pregestational diabetes may have a 12-fold increased risk of congenital heart disease than hers, but the fetus’s sensitivity to glucose oscillations makes it difficult to manage this condition clinically. It’s difficult.
Previous epidemiological studies have identified pregestational diabetes as a risk factor for other birth defects, including abnormalities of the central nervous system (CNS), gastrointestinal system, urogenital system, and musculoskeletal system.1
Physiologically relevant research
Over-reliance on animal models is due to limited access to human tissue in early-stage disease studies. However, it is unclear how accurately rodent models represent the abnormalities present in humans, as different species differ in heart size, cardiac physiology, electrophysiology, and bioenergetics.In addition, rodent models and many in vitro Cellular models rely on a progressive diabetic state, resulting in exaggerated features that are not clinically relevant.
“The study’s senior author, Dr. Aitor Aguirre from Michigan State University, said: “The new stem cell-based organoid technology employed enables physiologically relevant studies in humans, bypassing animal models to gain more information about relevant disease mechanisms, and accelerate drug discovery. ” and medical translation as well. ”
In the study, Dr. Aguirre and his colleagues used an advanced cardiac organoid model that represents human heart development during early pregnancy. This model, derived from human pluripotent stem cells (hPSCs), included ventricular formation, angiogenesis, cardiac tissue organization, and associated cardiac cell types. The research team modified the culture conditions to accurately reflect the patients’ reported physiological levels of glucose and insulin.
result
Pregestational diabetic heart organoids (PGDHOs) have developed features noted in previous mouse and human studies. Diabetic human heart organoids are larger and exhibit cardiac hypertrophy, the first hallmark of maternal pregestational diabetes. This was confirmed by studying the size of cardiomyocytes. Additionally, neonatal rats born to diabetic mothers exhibit arrhythmias and slow heart rates, which were also observed in PGDHO.
Single-cell transcriptomic analysis of PGDHO showed a reduced number of cardiomyocytes, a significant expansion of tissue on the outer surface of the heart, and a lack of well-developed vasculature during early developmental stages.
Furthermore, PGDHO showed increased accumulation of reactive oxygen species (ROS) and increased oxidative stress and mitochondrial swelling, which are hallmarks of diabetic fetal heart disease. A notable portion of ROS is localized to the ER, implying that its function may be impaired, resulting in ER stress.
At high and chronic levels of endoplasmic reticulum stress, the unfolded protein response (UPR) program ensures cell self-destruction. Similar to diabetes, chronic ER stress and defects in UPR signaling have emerged as major causes of human diseases such as neurodegeneration and cancer.2
Additionally, PGDHO has been shown to affect imbalances in very long chain fatty acids, especially omega-3 polyunsaturated fatty acids, which are largely synthesized in the ER. These findings indicate a large-scale ER-induced lipid imbalance in PGDHO. This imbalance is associated with the degradation of a lipid biosynthetic enzyme located in the ER called fatty acid desaturase 2 (FADS2) by the ER1-dependent mRNA degradation (RIDD) pathway. This pathway has been implicated in multiple other heart diseases.
Researchers tested several potential therapeutic compounds against PGDHO to ameliorate the effects of ER stress. A mixture of omega-3 fatty acids improved diabetic features, and targeting inositol-requiring enzyme 1 (IRE1) reduced cardiomyocyte hypertrophy. All compounds restored her FADS2 levels.
Dr. Aguirre said, “This organoid still lacks some features that may be important, such as external vascularization, outflow tracts, and better ventricular formation, which may be important in congenital heart disease or diabetic cardiomyopathy.” “There may still be some aspects missing.”
He concluded as follows: “On the one hand, we want to work with clinicians to establish the efficacy and safety of our study results in pregnant women. On the other hand, we want to use the organoid model to We hope to be able to apply it to other diseases that affect heart disease so that we can improve the lives of these children in the future.”
This study stem cell report.
References
1 Bao W, Du Y, Liu B; other. Associations between maternal pregestational and gestational diabetes and birth defects in newborns. diabetes care. [Internet] October 21, 2020 [2024 February 9];43(12):2983-90. Available from: https://doi.org/10.2337/dc20-0261
2 Oaks SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annual Review of Pathology: Mechanisms of Disease. [Internet] October 27, 2014 [2024 February 9];10:173-94. Available from: https://www.annualreviews.org/doi/abs/10.1146/annurev-pathol-012513-104649
