Congenital heart defects are the most prevalent human birth defects, and their incidence is exacerbated by maternal health conditions, such as diabetes during the first trimester (pregestational diabetes). Our understanding of the pathology of these disorders is hindered by a lack of human models and the inaccessibility of embryonic tissue. Using an advanced human heart organoid system, we simulated embryonic heart development under pregestational diabetes–like conditions. These organoids developed pathophysiological features observed in mouse and human studies before, including ROS-mediated stress and cardiomyocyte hypertrophy. scRNA-seq revealed cardiac cell-type-specific dysfunction affecting epicardial and cardiomyocyte populations and alterations in the endoplasmic reticulum and very-long-chain fatty acid lipid metabolism. Imaging and lipidomics confirmed these findings and showed that dyslipidemia was linked to fatty acid desaturase 2 mRNA decay dependent on IRE1-RIDD signaling. Targeting IRE1 or restoring lipid levels partially reversed the effects of pregestational diabetes, offering potential preventive and therapeutic strategies in humans.

中文翻译：

---

在人类心脏发育的类器官模型中，内质网应激和脂质失衡导致糖尿病胚胎心肌病

先天性心脏缺陷是最常见的人类出生缺陷，其发病率因孕产妇健康状况而加剧，例如妊娠早期的糖尿病（孕前糖尿病）。由于缺乏人体模型和难以获得胚胎组织，我们对这些疾病的病理学的理解受到阻碍。使用先进的人类心脏类器官系统，我们模拟了妊娠前糖尿病样条件下的胚胎心脏发育。这些类器官形成了之前在小鼠和人类研究中观察到的病理生理学特征，包括 ROS 介导的应激和心肌细胞肥大。scRNA-seq揭示了影响心外膜和心肌细胞群的心脏细胞类型特异性功能障碍以及内质网和超长链脂肪酸脂质代谢的改变。影像学和脂质组学证实了这些发现，并表明血脂异常与依赖于 IRE1-RIDD 信号传导的脂肪酸去饱和酶 2 mRNA 衰减有关。靶向 IRE1 或恢复血脂水平部分逆转了孕前糖尿病的影响，为人类提供了潜在的预防和治疗策略。