Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring
Vinothini Govindarajah, … , Mei Xin, Damien Reynaud
Vinothini Govindarajah, … , Mei Xin, Damien Reynaud
Published November 21, 2023
Citation Information: J Clin Invest. 2024;134(2):e169730. https://doi.org/10.1172/JCI169730.
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Research Article Hematology Inflammation

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

Abstract

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.

Authors

Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud

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Figure 2

GD promotes atherosclerosis development in adult offspring.

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GD promotes atherosclerosis development in adult offspring. (A) Experime...
(A) Experimental schematic used to assess atherosclerosis development in Apoe–/– GD offspring. (B) STZ-treated Apoe–/– dam nonfasting glycemia before and during pregnancy (n = 3). (C) Adult body weight (left panel) and nonfasting glycemia (right panel) of Apoe–/– offspring born to diabetic pregnancy (n = 4–7). (D) Histological criteria and atherosclerosis severity score in adult Ctrl and GD Apoe–/– offspring (n = 7–5/group). (E) Example of histological analysis of H&E-stained aortic valve from Apoe–/– offspring born to diabetic pregnancy compared with Ctrl. Original magnification, ×100; insets, ×200. (F) Experimental schematic used to assess atherosclerosis in Apoe–/– recipients transplanted with BM isolated from adult Ctrl and GD Apoe–/– offspring. (G) Adult body weight (left panel) and nonfasting glycemia (right panel) of Apoe–/– recipient mice transplanted with BM cells isolated from Ctrl or GD offspring (n = 5). (H) Atherosclerosis severity in Apoe–/– recipient mice (n = 11–12/group). (I) Example of histological analysis of aortic valve from Apoe–/– recipient mice. Original magnification, ×100. Data are represented as means ± SD (B, C, and G). Two-way ANOVA with Šidák’s post hoc test (B); χ2 test for trend (D and H). *P ≤ 0.05; **P ≤ 0.01.