Rovira i Virgili University, Tarragona, Spain.
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
Stem Cell Res Ther. 2021 Dec 20;12(1):608. doi: 10.1186/s13287-021-02678-y.
An environment of gestational diabetes mellitus (GDM) can modify the phenotype of stem cell populations differentially according to their placental localization, which can be useful to study the consequences for the fetus. We sought to explore the effect of intrauterine GDM exposure on the angiogenic properties of human amniotic membrane stem cells (hAMSCs).
We comprehensively characterized the angiogenic phenotype of hAMSCs isolated from 14 patients with GDM and 14 controls with normal glucose tolerance (NGT). Maternal and fetal parameters were also recorded. Hyperglycemia, hyperinsulinemia and palmitic acid were used to in vitro mimic a GDM-like pathology. Pharmacological and genetic inhibition of protein function was used to investigate the molecular pathways underlying the angiogenic properties of hAMSCs isolated from women with GDM.
Capillary tube formation assays revealed that GDM-hAMSCs produced a significantly higher number of nodes (P = 0.004), junctions (P = 0.002) and meshes (P < 0.001) than equivalent NGT-hAMSCs, concomitant with an increase in the gene/protein expression of FGFR2, TGFBR1, SERPINE1 and VEGFA. These latter changes were recapitulated in NGT-hAMSCs exposed to GDM-like conditions. Inhibition of the protein product of SERPINE1 (plasminogen activator inhibitor 1, PAI-1) suppressed the angiogenic properties of GDM-hAMSCs. Correlation analyses revealed that cord blood insulin levels in offspring strongly correlated with the number of nodes (r = 0.860; P = 0.001), junctions (r = 0.853; P = 0.002) and meshes (r = 0.816; P = 0.004) in tube formation assays. Finally, FGFR2 levels correlated positively with placental weight (r = 0.586; P = 0.028) and neonatal adiposity (r = 0.496; P = 0.014).
GDM exposure contributes to the angiogenic abilities of hAMSCs, which are further related to increased cord blood insulin and fetal adiposity. PAI-1 emerges as a potential key player of GDM-induced angiogenesis.
妊娠糖尿病（GDM）的环境可以根据其胎盘定位的不同，对干细胞群体的表型进行修饰，这对于研究对胎儿的影响很有帮助。我们试图探讨宫内 GDM 暴露对人羊膜间充质干细胞（hAMSCs）血管生成特性的影响。
我们全面表征了来自 14 名 GDM 患者和 14 名糖耐量正常（NGT）对照者的 hAMSCs 的血管生成表型。还记录了产妇和胎儿的参数。高血糖、高胰岛素血症和棕榈酸用于体外模拟 GDM 样病理学。药理学和基因抑制蛋白功能用于研究来自 GDM 妇女的 hAMSCs 的血管生成特性的分子途径。
毛细血管管腔形成试验显示，GDM-hAMSCs 形成的节点数（P = 0.004）、连接数（P = 0.002）和网孔数（P < 0.001）显著高于等效的 NGT-hAMSCs，同时 FGFR2、TGFBR1、SERPINE1 和 VEGFA 的基因/蛋白表达增加。这些变化在暴露于 GDM 样条件下的 NGT-hAMSCs 中得到重现。抑制 SERPINE1（纤溶酶原激活物抑制剂 1，PAI-1）的蛋白产物抑制了 GDM-hAMSCs 的血管生成特性。相关性分析显示，脐带血胰岛素水平与管腔形成试验中节点（r = 0.860；P = 0.001）、连接（r = 0.853；P = 0.002）和网孔（r = 0.816；P = 0.004）的数量呈强烈相关性。最后，FGFR2 水平与胎盘重量呈正相关（r = 0.586；P = 0.028）和新生儿肥胖（r = 0.496；P = 0.014）。
GDM 暴露有助于 hAMSCs 的血管生成能力，这进一步与脐带血胰岛素和胎儿肥胖增加有关。PAI-1 是 GDM 诱导血管生成的潜在关键因素。
