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: RRBS analysis on WT LSK cells isolated from the BM of adult offspring born to nomal and diabetic pregnancy

妊娠期糖尿病（Gestational diabetes）是一类常见的妊娠并发症，与不良围产期结局密切相关，且会增加子代成年后罹患代谢性疾病与动脉粥样硬化的风险。目前，这种延迟性病理传递的具体分子机制仍未阐明。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发展，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，但它们仍维持着与糖尿病相关的造血特征，提示其获得了持久性的糖尿病造血记忆。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与NLRP3炎性小体（NLRP3 inflammasome）的活性，二者可引发胎盘炎症水平显著升高。在子代成年个体中，该造血记忆与造血祖细胞内DNMT1的上调以及表观遗传改变密切相关。综上，本研究结果表明，造血系统可获得针对妊娠期糖尿病的持久性记忆，而该记忆是连接妊娠健康状态与成年期疾病发生的全新通路。
实验整体设计：对来自正常妊娠与糖尿病妊娠子代成年个体骨髓（bone marrow, BM）中分离的野生型（wild type, WT）LSK细胞进行RRBS（Reduced Representation Bisulfite Sequencing）分析。