# Diabetic Memory in Hematopoietic Stem Cells

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $432,397

## Abstract

PROJECT DESCRIPTION
One in six pregnancies is affected by some form of gestational diabetes (GD), a prevalence that is steadily rising
in the context of the worldwide epidemics of obesity and early diabetic onset. Early diagnosis and advances in
maternal glucose control have greatly mitigated the perinatal consequences of gestational diabetes on the
mothers and their offspring. However, these advances have only marginally impacted its long-term
consequences. As such, exposure to hyperglycemia in utero remains associated with increased long-term
morbidities in offspring. The mechanisms driving this pathological transmission across generations have not
been established. The overarching hypothesis of this project is that the hematopoietic stem cells (HSCs) of the
offspring are stably altered by gestational diabetes and are essential “effectors” of the long-term pathological
effects of gestational diabetes in offspring. Our preliminary data established two reliable mouse models of
gestational diabetes that reproduce not only the perinatal adverse features of the human pathology, but also its
long-term consequence in adult offspring. In these models, we show that gestational diabetes alters the
hematopoiesis of the offspring and that this effect persists to adulthood, even in absence of overt diabetes. This
phenotype indicates the acquisition of a long-lasting memory of metabolic events by the most upstream
hematopoietic stem cell (HSC) compartments. Importantly, our results also indicate that hematopoietic
alterations present in offspring can contribute to pathologies, such as atherosclerosis. Here we propose to
investigate the interplay between gestational diabetes and the hematopoietic system. Based on our preliminary
data, we will determine in aim 1 how signaling through the receptor of advanced glycation end products (RAGE)
contributes to the acquisition of a diabetic hematopoietic memory in GD offspring. In aim 2, we will establish the
epigenetic modifications that underlie the long-term maintenance of this hematopoietic memory in adult GD
offspring. Our work will decipher the mechanisms underlying the hematopoietic memory associated with
gestational diabetes. Defining these mechanisms will establish potential biomarkers for diabetic hematopoietic
memory. it will also reveal new therapeutic targets to alter the trajectory of the hematopoietic memory and prevent
its long-term pathological consequences.

## Key facts

- **NIH application ID:** 10808112
- **Project number:** 5R01DK133145-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Damien Reynaud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $432,397
- **Award type:** 5
- **Project period:** 2023-03-15 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808112

## Citation

> US National Institutes of Health, RePORTER application 10808112, Diabetic Memory in Hematopoietic Stem Cells (5R01DK133145-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10808112. Licensed CC0.

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