Extraembryonic heparin-binding epidermal growth factor-like growth factor deficiency compromises placentation in mice.
Extraembryonic heparin-binding epidermal growth factor-like growth factor deficiency compromises placentation in mice.
复制标题
胚胎外肝素结合表皮生长因子样生长因子缺乏会影响小鼠的胎盘形成。
DOI：
10.1093/biolre/ioy174
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发表时间：
2019
影响因子：
3.6
通讯作者：
Armant,DRandall
中科院分区：
文献类型：
--
作者：
Liu,Zitao;Skafar,DebraF;Kilburn,Brian;Das,SanjoyK;Armant,DRandall
肝素结合表皮生长因子 (EGF) 样生长因子 (HBEGF) 在植入部位的胚胎和子宫中表达，刺激胎盘形成所必需的滋养层侵袭活性。通过培育 Hbegf 无效突变杂合小鼠，研究了胚胎外 HBEGF 缺陷对胎盘发育的影响。在妊娠第 13.5 天，野生型 (Hbegf+/+) 和杂合子 (Hbegf+/-) 小鼠的平均胎盘重量分别约为 76 和 77 mg，而纯合子 (Hbgef−/−) 雌性小鼠的平均胎盘重量减少约 61 mg。相比之下，胎儿体重并没有受到基因型的显着影响。胎盘切片中的 HBEGF 免疫染色是 Hbegf 基因剂量依赖性的，而其他 EGF 家族成员的表达在 Hbegf+/+ 和 Hbegf−/− 胎盘中相当。组织学分析显示Hbegfnull胎盘的滋养层巨细胞没有明显差异，但与迷路相比，海绵滋养层区域减少（P<0.05）。虽然细胞凋亡没有差异，但通过核 Ki67 染色评估，增殖在 Hbegf−/− 胎盘的迷路中升高，而在海绵滋养层区域中降低。在用层粘连蛋白（毛细血管基底膜的标记物）染色的Hbegf−/–胎盘中，迷宫形态出现破坏，并且毛细血管密度降低。免疫组织化学染色显示 Hbegf−/− 胎盘的海绵滋养层和迷路区域的血管内皮生长因子 (VEGF) 水平降低 (P < 0.01)。在体外，补充 HBEGF 会增加人滋养层细胞系中 VEGF 的表达。这些发现表明，滋养层 HBEGF 通过在小鼠发育中的胎盘中诱导 VEGF 来促进胎盘毛细血管的形成。
Heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) is expressed in the embryo and uterus at the implantation site, stimulating trophoblast invasive activity essential for placentation. The effect of extraembryonic HBEGF deficiency on placental development was investigated by breeding mice heterozygous for theHbegfnull mutation. On gestation day 13.5, the average placental weights of the wild-type (Hbegf+/+) and heterozygous (Hbegf+/−) mice were approximately 76 and 77 mg, respectively, as opposed to reduced average placental weights of approximately 61 mg in homozygous null (Hbgef−/−) females. In contrast, fetal weights were not significantly affected by genotype. HBEGF immunostaining in placental sections wasHbegfgene dosage-dependent, while expression of other EGF family members was comparable inHbegf+/+andHbegf−/−placentas. Histological analysis revealed no apparent differences in trophoblast giant cells, but the spongiotrophoblast region was reduced compared to labyrinth (P< 0.05) inHbegfnull placentas. While no differences in cell apoptosis were noted, proliferation as assessed by nuclear Ki67 staining was elevated in the labyrinth and decreased in the spongiotrophoblast region ofHbegf−/−placentas. Labyrinth morphology appeared disrupted inHbegf−/–placentas stained with laminin, a marker for capillary basement membrane, and the capillary density was reduced. Immunohistochemical staining revealed reduced vascular endothelial growth factor (VEGF) levels in both spongiotrophoblast and labyrinth (P< 0.01) regions ofHbegf−/−placentas. In vitro, HBEGF supplementation increases the expression of VEGF in a human trophoblast cell line. These findings suggest that trophoblast HBEGF promotes placental capillary formation by inducing VEGF in the developing placenta of mice.