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 advanced glycation end product receptor (AGER) and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which lead to increased placental inflammation. In adult offspring, we find that this memory is associated with DNA methyltransferase 1 (DNMT1) upregulation and epigenetic changes in hematopoietic progenitors. Together, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes and that this memory constitutes a pathway connecting gestational health to adult pathologies.

中文翻译：

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小鼠妊娠糖尿病会诱发造血记忆，影响后代的长期健康

妊娠糖尿病是一种常见的妊娠并发症，与不良的围产期结局以及成年后代患代谢疾病和动脉粥样硬化的风险增加有关。造成这种迟发性病理传播的机制仍不清楚。在小鼠模型中，我们发现糖尿病妊娠所生的成年后代动脉粥样硬化的发展可能部分与造血改变有关。尽管它们没有表现出任何明显的代谢紊乱，但成年后代仍保持与糖尿病相关的造血特征，表明获得了持久的糖尿病造血记忆。我们发现，妊娠期间这种造血记忆的诱导依赖于晚期糖基化终末产物受体（AGER）和核苷酸结合和寡聚化结构域样受体家族含pyrin结构域3（NLRP3）炎性体的活性，这会导致胎盘炎症。在成年后代中，我们发现这种记忆与 DNA 甲基转移酶 1 (DNMT1) 上调和造血祖细胞的表观遗传变化有关。总之，我们的结果表明，造血系统可以获得妊娠糖尿病的持久记忆，并且这种记忆构成了将妊娠健康与成人病理联系起来的途径。