胚発生および着床現象における細胞成長因子の意義に関する研究(<シンポジウム>妊娠の成立機構 : 胚発生から着床まで)

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Although it has been reported that growth factor and extracellular matrix (ECM) play an important role in the control of cell proliferation and differentiation in general, their involvement in the regulation of early embryogenesis and implantation is poorly understood. In order to clarify the mechanism underlying establishment and maintenance of pregnancy, the effect of EGF, TGF-α, TGF-β, TN (tenascin) on the development of preimplantation embryo and endometrial function were investigated. 1. Growth factors in early embryogenesis. EGF did not exert any significant effect on the development of mouse 2-cell embryo in vitro. RT-PCR revealed the presence of EGFmRNA in blastocyst and 2-cell embryo, in which it may be derived from maternal genome. PA-1 cells, human teratocarcinoma-derived cell line, share biochemical characteristics with embryo developed at and beyond blastocyst stage. Anti-EGF antibody but not EGF exerted inhibitory effect on DNA synthesis in PA-1 cell, which produced and secreted immunoreactive and bioactive EGF and contained high-affinity EGF receptor. These results indicate that autocrine/paracrine mechanism of EGF action may be a key regulation of embryo development at and beyond blastocyst stage. 2. Growth factors and ECM in implantation. The luminal fluid in DES-stimulated mouse uterus contained high concentrations of EGF and TGF-α. In vivo administration of EGF, like estrogen, stimulated uterine epithelial proliferation as well as progesterone receptor levels. In vivo administration of anti-EGF antibody or anti-TGF-α antibody significantly reduced estrogen-induced labelling index in castrated mouse uterus. The concomitant administration of TGF-β_1 and TGF-β_2 with estrogen further stimulated DNA synthesis in the mouse uterus than estrogen alone. These results suggest that growth factors partly may be a mediator of estrogen actions on the uterine cell proliferation and the induction of progesterone receptor, which are important preparative steps for implantation. Northern blotting and in situ hybridization using cDNA probe for mouse prepro EGF revealed the presence of prepro EGFmRNA in the early pregnant mouse uterus, especially in stroma/decidua in Day 6 of pregnancy. EGF and TGF-α significantly stimulated trophoblast outgrowth of the mouse blastocyst in vitro in supplementation with 0.1% of fetal bovine serum. The specific binding of EGF was detected in the outgrown trophoblastic cells and inner cell mass of cultured blastocysts by autoradiography. From these findings, it may be possible that EGF produced in stromal/decidual cells exerts stimulatory effect on trophoblast outgrowth, playing an important role in the interaction between embryo and endometrium. Both immunohistochemical and in situ hybridization observations of early pregnant mouse uterus revealed that extracellular matrix TN containing EGF-like domain was expressed in subepithelium in Day 1〜4 and in circular muscle layer in Day 5〜6 of pregnancy. Northern blot hybridization showed 2 types of alternatively spliced variants of TNmRNA ; TNmRNA of 7Kb variant, predominantly expressed in subepithelium, may have a function for tissue repair of uterine epithelial cell to implantation, whereas the biological action of 5.5Kb variant in muscle layer seems to be expressed for the resistence to enlargement of uterine volume due to decidualization. 3. Growth factors in decidualization. The decidualization process is an important final stage of establishment of pregnancy. The maximum number of binding sites of EGF receptor in the human endometrium increased during both in vivo and in vitro decidualization while dissociation constant remained unchanged. EGF stimulated DNA synthesis of cultured decidual cells. EGFmRNA and TGF-αmRNA were possitively expressed only after decidualization, which was also confirmed in situ hybridizatin and in protein level. MPA-induced in vitro decidualized cells also contained EGFmRNA. These results indicate EGF regulates
社団法人日本産科婦人科学会の論文
1992-08-01

胚発生および着床現象における細胞成長因子の意義に関する研究(<シンポジウム>妊娠の成立機構 : 胚発生から着床まで)

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