Placental nanoparticle gene therapy normalizes gene expression changes in the fetal liver associated with fetal growth restriction in a fetal sex-specific manner.
Placental nanoparticle gene therapy normalizes gene expression changes in the fetal liver associated with fetal growth restriction in a fetal sex-specific manner.
复制标题
胎盘纳米颗粒基因治疗以胎儿性别特异性的方式使胎儿肝脏中与胎儿生长受限相关的基因表达变化正常化。
DOI：
10.1017/s2040174423000016
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发表时间：
2023
影响因子：
1.7
通讯作者：
Jones,HelenN
中科院分区：
文献类型：
--
作者：
Wilson,RebeccaL;Stephens,KendalK;Jones,HelenN
胎儿生长受限（FGR）与患非传染性疾病的风险增加有关。我们有一个胎盘特异性纳米颗粒基因治疗方案，增加胎盘表达的人胰岛素样生长因子1（hIGF 1），用于治疗子宫内FGR。我们的目的是在FGR建立的早期阶段表征FGR对肝脏新生途径的影响，并确定胎盘纳米颗粒介导的hIGF 1治疗是否可以解决FGR胎儿的差异。雌性Hartley豚鼠（母鼠）采用既定方案饲喂对照或母体营养限制（MNR）饲料。在GD 30 -33，母鼠接受超声引导的经皮胎盘内注射hIGF 1纳米颗粒或PBS（假手术），并在注射后5天处死。将胎肝组织固定并快速冷冻用于形态学和基因表达分析。在雌性和雄性胎儿中，MNR降低了肝脏重量占体重的百分比，而hIGF 1纳米颗粒治疗没有改变。在雌性胎肝中，MNR组缺氧诱导因子1（HIF 1 α）和肿瘤坏死因子（TNFα）的表达较对照组增加，而MNR + hIGF 1组较MNR组减少。在雄性胎肝中，与对照组相比，MNR增加了Igf 1的表达，降低了Igf 2的表达。在MNR + hIGF 1组中，Igf 1和Igf 2表达恢复到对照水平。这些数据提供了对FGR胎儿中观察到的性别特异性机制适应的进一步了解，并表明对胎儿发育机制的破坏可以通过胎盘治疗恢复正常。
Fetal growth restriction (FGR) is associated with increased risk of developing non-communicable diseases. We have a placenta-specific nanoparticle gene therapy protocol that increases placental expression of human insulin-like growth factor 1 (hIGF1), for the treatment of FGR in utero. We aimed to characterize the effects of FGR on hepatic gluconeogenesis pathways during early stages of FGR establishment, and determine whether placental nanoparticle-mediated hIGF1 therapy treatment could resolve differences in the FGR fetus. Female Hartley guinea pigs (dams) were fed either a Control or Maternal Nutrient Restriction (MNR) diet using established protocols. At GD30-33, dams underwent ultrasound guided, transcutaneous, intraplacental injection of hIGF1 nanoparticle or PBS (sham) and were sacrificed 5 days post-injection. Fetal liver tissue was fixed and snap frozen for morphology and gene expression analysis. In female and male fetuses, liver weight as a percentage of body weight was reduced by MNR, and not changed with hIGF1 nanoparticle treatment. In female fetal livers, expression of hypoxia inducible factor 1 (Hif1α) and tumor necrosis factor (Tnfα) were increased in MNR compared to Control, but reduced in MNR + hIGF1 compared to MNR. In male fetal liver, MNR increased expression of Igf1 and decreased expression of Igf2 compared to Control. Igf1 and Igf2 expression was restored to Control levels in the MNR + hIGF1 group. This data provides further insight into the sex-specific mechanistic adaptations seen in FGR fetuses and demonstrates that disruption to fetal developmental mechanisms may be returned to normal by treatment of the placenta.