Kostina Aleksandra, Lewis-Israeli Yonatan R, Abdelhamid Mishref, Gabalski Mitchell A, Volmert Brett D, Lankerd Haley, Huang Amanda R, Wasserman Aaron H, Lydic Todd, Chan Christina, Olomu Isoken, Aguirre Aitor
Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.
Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA.
bioRxiv. 2023 Jun 8:2023.06.07.544081. doi: 10.1101/2023.06.07.544081.
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.
先天性心脏缺陷是人类最常见的出生缺陷，影响约1%的活产婴儿。孕期前的一些母体状况会加剧先天性心脏缺陷的发病率，比如孕早期患糖尿病。由于缺乏人类模型以及在相关阶段难以获取人体组织，我们从机制上理解这些疾病的能力受到严重限制。在此，我们使用了一种先进的人类心脏类器官模型，该模型概括了孕早期心脏发育的复杂方面，以模拟孕前糖尿病对人类胚胎心脏的影响。我们观察到，糖尿病条件下的心脏类器官出现了病理生理特征，如先前在小鼠和人类研究中报道的那些特征，包括活性氧介导的应激和心肌细胞肥大等。单细胞RNA测序揭示了影响心外膜和心肌细胞群体的心脏细胞类型特异性功能障碍，并提示内质网功能和极长链脂肪酸脂质代谢发生改变。共聚焦成像和液相色谱-质谱联用脂质组学证实了我们的观察结果，并表明血脂异常是由依赖于肌醇需求酶1- regulated IRE1-dependent decay（RIDD）信号传导的脂肪酸去饱和酶2（FADS2）mRNA降解介导的。我们还发现，使用针对肌醇需求酶1或恢复类器官内健康脂质水平的药物干预措施，孕前糖尿病的影响在很大程度上可以得到逆转，这为人类新的预防和治疗策略打开了大门。
