Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta
Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta
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DOI：
10.1152/ajpcell.00035.2008
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发表时间：
2008-06-01
影响因子：
5.5
通讯作者：
Aplin, John D.
中科院分区：
文献类型：
--
作者：
Forbes, Karen;Westwood, Melissa;Aplin, John D.
人类妊娠的主要疾病根源于胎盘缺陷。正常的胎盘发育依赖于细胞滋养细胞的增殖、分化和融合，以形成和维持覆盖在胎盘上的合胞滋养细胞。有间接证据表明，在妊娠障碍中异常的胰岛素样生长因子（IGFs）参与调节滋养细胞的更新，但控制人类胎盘生长的过程尚不清楚。利用维持细胞群之间空间和本体关系的人妊娠早期胎盘绒毛外植体模型，我们证明了IGF-I/IGF-II可以增强细胞滋养层细胞的增殖，并且这两种因子都可以拯救细胞滋养层细胞免于凋亡。在缺乏合胞滋养层细胞的情况下，细胞滋养层细胞的增殖会停止，尽管当暴露于IGF时，剥落的细胞滋养层细胞可以增殖，细胞滋养层细胞分化/融合的速率以及合胞再生的速率会增加。信号抑制剂的使用表明，IGFs通过MAPK途径介导其对细胞滋养层细胞增殖/合胞体形成的影响，而对存活的影响则由磷酸肌苷3激酶途径调节。这些结果表明，细胞滋养细胞和合胞体之间的定向接触在调节两种细胞群的相对数量方面是重要的。然而，IGF可以对胎盘生长/发育施加外源性调节影响，这表明操纵胎盘IGF轴可能为纠正胎盘生长不足提供一种潜在的治疗途径。
The main disorders of human pregnancy are rooted in defective placentation. Normal placental development depends on proliferation, differentiation, and fusion of cytotrophoblasts to form and maintain an overlying syncytiotrophoblast. There is indirect evidence that the insulin-like growth factors (IGFs), which are aberrant in pregnancy disorders, are involved in regulating trophoblast turnover, but the processes that control human placental growth are poorly understood. Using an explant model of human first-trimester placental villus in which the spatial and ontological relationships between cell populations are maintained, we demonstrate that cytotrophoblast proliferation is enhanced by IGF-I/IGF-II and that both factors can rescue cytotrophoblast from apoptosis. Baseline cytotrophoblast proliferation ceases in the absence of syncytiotrophoblast, although denuded cytotrophoblasts can proliferate when exposed to IGF and the rate of cytotrophoblast differentiation/fusion and, consequently, syncytial regeneration, increases. Use of signaling inhibitors suggests that IGFs mediate their effect on cytotrophoblast proliferation/syncytial formation through the MAPK pathway, whereas effects on survival are regulated by the phosphoinositide 3-kinase pathway. These results show that directional contact between cytotrophoblast and syncytium is important in regulating the relative amounts of the two cell populations. However, IGFs can exert an exogenous regulatory influence on placental growth/development, suggesting that manipulation of the placental IGF axis may offer a potential therapeutic route to the correction of inadequate placental growth.