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 5

AGER and NLRP3 function are necessary for the induction of the GD hematopoietic memory in offspring.

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AGER and NLRP3 function are necessary for the induction of the GD hemato...
(A) Schematic of the experimental design. (B–D) Hematopoietic readout for offspring born to normal or diabetic pregnancy: absolute numbers of BM GMP cells (left graphs) and absolute numbers of BMDMs in culture 24 hours after treatment with PBS or LPS/IFN-γ (right graphs) in WT (B) (data also presented in Supplemental Figure 3D and Figure 4F), Ager–/– (C), and Nlrp3–/– backgrounds (D). (C: n = 8–10 for GMP; n = 10–20 for BMDM; D: n = 6 for GMP, n = 6–12 for BMDM). (E) Immune cell composition in placenta: percentages in CD45+ cells (n = 4–7/group). (F) RT-PCR analysis showing the expression of the Il6 and Ccl2 inflammatory cytokine genes. Results are expressed as fold change relative to Ctrls, set at 1 (n = 3). (G) RNA-Seq analysis on placental CD45+ cells isolated at G17 from Ctrl, WTSTZ, and Nlrp3STZ dams (n = 3/group). Principal component analysis (PCA) of RNA-Seq data (left panel). Differential gene signature: heatmap using differentially expressed genes (DEGs) with log2FC> |0.58| and FDR < 0.05 in all comparisons (central panel). GSEA of genes differentially expressed in WTSTZ cells compared with Ctrl and Nlrp3STZ conditions (right panel). Data are represented as means ± SD. Unpaired 2-tailed Student’s t tests (B–D, left graphs); 1-way ANOVA with Tukey’s post hoc test (F) or 2-way ANOVA with Šidák’s post hoc test (B–D, right graphs; E). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.0005; ****P ≤ 0.0001.