Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring
Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud
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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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 3

Offspring born to diabetic pregnancy display altered steady-state hematopoiesis.

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Offspring born to diabetic pregnancy display altered steady-state hemato...
(A) Schematic of the murine hematopoietic hierarchy. (B) BM cellularity and absolute numbers of BM myeloid/lymphoid cells in adult WTAkita offspring (n = 12). (C and D) Absolute numbers of HSPC populations in the BM of adult Ctrl and WTAkita offspring (n = 11–12). CMP, common myeloid progenitor (Lineage–c-Kit+Sca-1–CD34+FcγR–); MEP, megakaryocyte/erythroid progenitor (Lineage–c-Kit+Sca-1–CD34–FcγR–). (E) Percentage of HSC distribution in cell-cycle phases in adult Ctrl and WTAkita offspring. Right panel shows representative FACS plots for Ki67/ Hoechst 33342 staining (n = 10). (F) Percentage of HSCs isolated from Ctrl and WTAkita offspring that present FOXO3 nuclear localization at steady state (n = 6 with 50 individual cells analyzed for each). Right panel shows representative images of FOXO3 immunofluorescence analysis. Scale bar: 10 μm. (G and H) Competitive hematopoietic reconstitution assay for HSCs isolated from Ctrl (n = 6) and WTAkita (n = 7) offspring from 1 experiment: PB chimerism over time (G) and BM chimerism for HSC subsets, 20 weeks after transplantation (H). Data are represented as means ± SD. Two-way ANOVA with Šidák’s post hoc test (B, C, D, G, and H) or with Tukey’s post hoc test (E); unpaired 2-tailed Student’s t test (F). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.0005; ****P ≤ 0.0001.