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 4

GD altered the inflammatory hematopoietic response in offspring.

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GD altered the inflammatory hematopoietic response in offspring. (A) Sch...
(A) Schematic of the experimental design for the in vivo LPS inflammatory challenge. (B) BM cellularity and absolute numbers of BM myeloid cells 3 days after LPS treatment. (C) Absolute numbers of BM MPP3 and GMP cells 3 days after LPS treatment (n = 3–6/group). (D) Inflammatory cytokine concentration in the mouse serum 3 days after LPS treatment (n = 4/group). (E) Schematic of experimental design to generate and activate BMDMs. (F) Absolute numbers of BMDMs in culture 24 hours after treatment with PBS or LPS/IFN-γ (n = 4–9/group). (G) Schematic of experimental design describing BMDM generation from transplanted mice. (H) Following transplantation, absolute numbers of BMDMs in culture 24 hours after treatment with PBS or LPS/IFN-γ (n = 4/group). Data are represented as means ± SD. One-way ANOVA with Tukey’s post hoc test (B and C) or 2-way ANOVA with Šidák’s post hoc test (D, F and G). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.0005; ****P ≤ 0.0001.