(52) Impact of IL-10 on sex-specific changes in hematopoietic stem and progenitor cell function in offspring of obese mice

Background: Children born to mothers with obesity are at higher risk of developing diseases such as obesity, type 2 diabetes, asthma, and leukemia. These diseases share common features of immune dysfunction and altered hematopoiesis, highlighting the potential impact of maternal obesity exposure on offspring hematopoietic stem and progenitor cell (HSPC) function. We have previously shown that male offspring has HSPC dysfunction as a result of maternal obesity exposure. However, mechanisms underlying sex-specific changes in HSPC function have not been studied.

Objectives: This study aims to test the hypothesis that sex-specific differences in HSPC function in offspring of obese mice are associated with transcriptome changes and IL-10 has an essential role in HSPC reprogramming.

Design/Methods: Female dams were fed with chow (Con) or Western diet (MatOb) for 4 weeks before mating, through pregnancy, and lactating period. For RNAseq, HSPC (Lin- Sca-1+ cKit+ cells) were flow-sorted from offspring bone marrow on postnatal day 21 (p21). Differentially expressed genes (DEG) were determined using DESeq2 (adjusted p-value < 0.05) and subjected to fast gene set enrichment analysis (fgsea). To assess HSPC function in male offspring treated with exogenous IL-10 on p14, a competitive repopulation assay was performed after flow-sorting HSPC on p21 and transplanting into lethally irradiated mice.

Results: RNAseq revealed 100 DEG in male MatOb HSPC, and 1788 DEG in female MatOb HSPC (n=6/sex/group) compared to same-sex Con. Fgsea revealed a strong upregulation of genes associated with production of IL-10 in female MatOb offspring LSK cells while male MatOb offspring did not exhibit significant changes. We also found that IL-10 was significantly increased in P21 female MatOb offspring (n=8-10/sex/group) and recipient animals received LSK from female MatOb offspring (n=3-5/group) compared to same-sex Con. Next, using a competitive repopulation assay, we sought to determine if exogenous IL-10 can rescue HSPC dysfunction in male MatOb offspring. Compared to same-sex Con and MatOb offspring treated with PBS, HSPC from male MatOb treated with IL-10 had higher donor chimerism following secondary transplantation.

Conclusion: Sex-specific alterations in offspring HSPC function secondary to maternal obesity exposure are associated with transcriptome changes. Furthermore, increased IL-10 production exerts a protective effect against HSPC dysfunction in female MatOb offspring. Future experiments are directed to assess downstream effector nodes of IL-10 and validate potential compensatory effects of IL-10 by blocking IL-10 in female offspring.