Transforming growth factor-beta stimulates trophoblast oncofetal fibronectin synthesis in vitro: implications for trophoblast implantation in vivo.
Transforming growth factor-beta stimulates trophoblast oncofetal fibronectin synthesis in vitro: implications for trophoblast implantation in vivo.
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DOI：
10.1210/jcem.78.5.8175984
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发表时间：
1994-05
期刊：
影响因子：
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通讯作者：
R. Feinberg;H. Kliman;Cai-Liang Wang
中科院分区：
文献类型：
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作者：
R. Feinberg;H. Kliman;Cai-Liang Wang
在妊娠组织中，癌胚纤连蛋白（onfFN）已被特异性地定位于胎盘-子宫交界处和绒毛膜的绒毛外锚定滋养细胞周围的细胞外基质（ECM）。当从妊娠早期或晚期胎盘中分离时，培养的人细胞滋养层细胞分泌并存款在ECM中的fFN上。此外，onfFN合成响应于血清刺激因子而显著上调。本研究的目的是研究转化生长因子β（TGF β），一种存在于子宫蜕膜中的细胞因子，作为滋养层分泌FN的刺激因子的作用。我们对TGF β的意义的初步认识来自于一名患有严重同种免疫性血小板减少症的新生儿的脐带血清的偶然使用。在含此血清的培养基中培养的滋养层细胞进行正常的形态分化，但产生的onfFN明显减少。以类似的方式，在与抗TGF β中和抗体预孵育的正常血清中培养的滋养层也产生显著更少的onfFN。外源性加入TGF β 1可使滋养层细胞在含有血小板减少血清的培养基中产生onfFN的能力恢复4- 5倍。在来自人或牛血浆的血小板贫乏血清中，TGF β 1也诱导onfFN合成，如在条件培养基中和通过onfFN在细胞相关ECM原纤维中的免疫细胞化学定位所测定的。剂量反应分析表明，onfFN刺激反应对TGF β敏感，ED 50为0.1-0.2 ng/ml。以相互作用的方式，TGF β抑制β hCG分泌3至4倍。我们的研究结果表明，TGF β是滋养层分泌fFN的重要刺激因子。此外，TGF β似乎通过上调锚定滋养层标志物（onfFN）的表达和下调绒毛合胞体滋养层（hCG β）的表型标志物来调节滋养层分化。我们推测，滋养层对TGF β的反应在植入环境中通过刺激滋养层来源的植入部位纤连蛋白的产生而促进滋养层粘附。
In pregnancy tissues, oncofetal fibronectin (onfFN) has been localized specifically to the extracellular matrix (ECM) surrounding extravillous anchoring trophoblasts of the placental-uterine junction and chorion. When isolated from first or third trimester placentas, human cytotrophoblasts in culture secrete and deposit onfFN in the ECM. In addition, onfFN synthesis is significantly up-regulated in response to serum stimulatory factor(s). The goal of this study was to examine the role of transforming growth factor-beta (TGF beta), a cytokine present in uterine decidua, as a stimulator of trophoblast onfFN production. Our initial insight into the significance of TGF beta resulted from the serendipitous use of cord serum from a neonate with severe alloimmune thrombocytopenia. Trophoblasts cultured in medium containing this serum underwent normal morphological differentiation, but produced markedly less onfFN. In an analogous fashion, trophoblasts cultured in normal serum preincubated with anti-TGF beta neutralizing antibodies also produced significantly less onfFN. Exogenously added TGF beta 1 restored the ability of trophoblasts to produce onfFN by a factor of 4- to 5-fold in medium containing thrombocytopenic serum. In platelet-poor serum derived from human or bovine plasma, TGF beta 1 also induced onfFN synthesis, as assayed both in the conditioned medium and by immunocytochemical localization of onfFN in cell-associated ECM fibrils. Dose-response analysis demonstrated that the onfFN stimulatory response is sensitive to TGF beta, with an ED50 of 0.1-0.2 ng/ml. In a reciprocal fashion, TGF beta inhibited beta hCG secretion 3- to 4-fold. Our results demonstrate that TGF beta is a significant stimulator of trophoblast onfFN production. Furthermore, TGF beta appears to modulate trophoblast differentiation by up-regulating the expression of an anchoring trophoblast marker (onfFN) and down-regulating a phenotypic marker of villous syncytiotrophoblast (hCG beta). We speculate that trophoblast responsiveness to TGF beta in the implantation milieu contributes to trophoblast adhesion by stimulating the production of a trophoblast-derived implantation site fibronectin.