Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring. Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring

Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the pattern recognition receptor AGER and the NLRP3 inflammasome, which leads to increased placental inflammation. In adult offspring, we find that this memory is associated with DNMT1 upregulation and epigenetic changes in hematopoietic progenitors. Altogether, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes, and that this memory constitutes a new pathway connecting gestational health to adult pathologies. Overall design: RNA-seq analysis on placental CD45+ cells isolated from Ctrl, WT(STZ) and Nlrp3(STZ) E17 embryos.

妊娠期糖尿病（Gestational Diabetes）是一类常见的妊娠并发症，与不良围产期结局以及子代成年后罹患代谢性疾病和动脉粥样硬化（atherosclerosis）的风险升高密切相关。目前介导这一延迟性病理传递的具体机制仍不明晰。在小鼠模型中，本研究发现糖尿病妊娠子代成年后动脉粥样硬化的发生，可部分归因于造血系统的异常改变。尽管这些子代未表现出明显的代谢紊乱，但成年后仍维持与糖尿病相关的造血特征，提示其获得了持久的糖尿病性造血记忆。本研究证实，妊娠期间该造血记忆的诱导依赖于模式识别受体（pattern recognition receptor）AGER和NLRP3炎性小体（NLRP3 inflammasome）的活性，二者可引发胎盘炎症水平升高。在子代成年后，本研究发现该记忆与造血祖细胞中DNMT1的表达上调以及表观遗传改变相关。综上，本研究结果证实，造血系统可获得对妊娠期糖尿病的持久记忆，且该记忆构成了连接妊娠期健康与成年期疾病的全新通路。整体实验设计：对从对照组（Ctrl）、野生型STZ处理组（WT(STZ)）及Nlrp3(STZ)组的E17胚胎中分离的胎盘CD45+细胞（CD45+ cells）开展RNA测序（RNA-seq）分析。