Abstract
Fetal programming has been proposed as a key mechanism underlying the association between intrauterine exposure to maternal diabetes and negative health outcomes in offspring. To determine whether gestational diabetes mellitus (GDM) might leave an imprint in fetal precursors of the amniotic membrane and whether it might be related to adverse outcomes in offspring, a prospective case‐control study was conducted, in which amniotic mesenchymal stem cells (AMSCs) and resident macrophages were isolated from pregnant patients, with either GDM or normal glucose tolerance, scheduled for cesarean section. After characterization, functional characteristics of AMSCs were analyzed and correlated with anthropometrical and clinical variables from both mother and offspring. GDM‐derived AMSCs displayed an impaired proliferation and osteogenic potential when compared with control cells, accompanied by superior invasive and chemotactic capacity. The expression of genes involved in the inflammatory response (TNFα, MCP‐1, CD40, and CTSS) was upregulated in GDM‐derived AMSCs, whereas anti‐inflammatory IL‐33 was downregulated. Macrophages isolated from the amniotic membrane of GDM mothers consistently showed higher expression of MCP‐1 as well. In vitro studies in which AMSCs from healthy control women were exposed to hyperglycemia, hyperinsulinemia, and palmitic acid confirmed these results. Finally, genes involved in the inflammatory response were associated with maternal insulin sensitivity and prepregnancy body mass index, as well as with fetal metabolic parameters. These results suggest that the GDM environment could program stem cells and subsequently favor metabolic dysfunction later in life. Fetal adaptive programming in the setting of GDM might have a direct negative impact on insulin resistance of offspring.
Highlights
Gestational diabetes mellitus (GDM) is associated both with short-term adverse obstetric and perinatal complications and with long-term metabolic health consequences for offspring.[1]
We found an association between the biological features of these fetal precursor cells and the maternal and fetal clinical and metabolic parameters, supporting the notion that fetal adaptive programming in the setting of GDM might have a direct impact on offspring
We show that GDM results in a deregulation of genes involved in inflammation in amniotic mesenchymal stem cells (AMSCs), which have been associated with the development of insulin resistance, type 2 diabetes, obesity, and atherosclerosis, as well as with pro-inflammatory changes of amniotic membrane-resident macrophages
Summary
Gestational diabetes mellitus (GDM) is associated both with short-term adverse obstetric and perinatal complications and with long-term metabolic health consequences for offspring.[1]. The amniotic membrane is the innermost layer of the placenta and possesses anti-inflammatory and antibacterial properties that contribute to materno-fetal tolerance It exerts many metabolic functions, such as the transport of water and soluble molecules and the production of bioactive factors.[9] Our study sought to investigate whether GDM might leave an imprint in fetal precursors found in the amniotic membrane and, if so, whether it might be related to adverse outcomes in offspring. We focused on amniotic mesenchymal stem/stromal cells (AMSCs) which are mainly characterized by their low immunogenicity, immunomodulatory properties and mesodermal multilineage differentiation capacity in vitro.[10] We report evidence that maternal metabolic derangements during gestation disturb the biological properties of AMSCs. Of note, we found an association between the biological features of these fetal precursor cells and the maternal and fetal clinical and metabolic parameters, supporting the notion that fetal adaptive programming in the setting of GDM might have a direct impact on offspring
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