Gestational diabetes impacts fetal precursor cell responses with potential consequences for offspring

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.

The angiogenic properties of human amniotic membrane stem cells are enhanced in gestational diabetes and associate with fetal adiposity

“…This situation obviously limited our ability to investigate differences in metabolic parameters between the groups. Another limitation of our study is the relatively small sample size; however, it is substantially larger than other studies analyzing the plasticity of placental-derived mesenchymal stromal cells [ 9 , 13 , 14 , 25 ]. Finally, we cannot discard the possibility that the stemness and angiogenic abilities of the hAMSCs were affected by cryopreservation and serial passaging [58], but as the same protocol was applied to GDM- and NGT-derived hAMSCs it should not affect our results.…”

“…Surface markers of the mesenchymal lineage were determined and analyzed by flow cytometry (FACS Aria III; BD Biosciences, San Jose, CA) meeting the minimum criteria defined by the International Society of Cell Therapy [ 28 ]. Briefly, hAMSCs (1 × 10 5 ) were incubated with a panel of primary antibodies (BD Pharmingen, San Diego, CA) as described [ 14 ]. Data analysis was performed using FACSDiva software (BD Biosciences).…”

“…It has been also described that GDM alters the transcriptional profile [ 12 ] and mitochondrial activity [ 11 , 13 ] of these precursor cell populations. In this context, we recently demonstrated that GDM disturbs the multilineage differentiation potential and immunomodulatory properties of human amniotic MSCs (hAMSCs) [ 14 ], which are located in a privileged region in close contact with the amniotic fluid and the fetus. We also found that the inflammatory status of hAMSCs was related not only to maternal metabolic cues, but also to infant clinical and metabolic status [ 14 ], indicating that hAMSCs might be a powerful tool for the indirect study of fetal cells in the context of hyperglycemia and insulin resistance.…”

What is the Influence of Maternal Weight Gain in Different Gestational Clinical Conditions on the Prole Weight in Pre-School Age?

“…Previous publications on the topic reported that maternal over-nutrition during pregnancy has repercussions on the child health the medium and long term, since metabolic changes that occur during fetal development can generate epigenetic changes, which will play an important role in the prevalence of transmitted obesity across generations. The conclusions of these articles reinforced the importance of weight control, both before and during pregnancy, and consumption of healthy foods in this period can reduce the risks of fetal programming of metabolic diseases [22][23][24].…”

Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3+/Pod+/CD11b+ Cells) in Patient with Preeclampsia

“…However, the underlying mechanism is poorly understood. The most promising hypothesis is that suboptimal intrauterine environments during pregnancy with PE may permanently alter the organ structure and biological feedback mechanism of the fetus, increasing the individual’s susceptibility to disease [ 42 , 43 ], and that stem cells may be involved in the influence of the in utero environment on the subsequent risk of disease onset in adult life [ 44 , 45 ].…”