Feinberg R F, Kliman H J, Wang C L
Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia 19104-4283.
J Clin Endocrinol Metab. 1994 May;78(5):1241-8. doi: 10.1210/jcem.78.5.8175984.
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.
在妊娠组织中，癌胚纤连蛋白（onfFN）已被特异性定位到胎盘 - 子宫交界处和绒毛膜的绒毛外锚定滋养层细胞周围的细胞外基质（ECM）中。当从妊娠早期或晚期胎盘分离时，培养的人细胞滋养层细胞在细胞外基质中分泌并沉积onfFN。此外，onfFN的合成在血清刺激因子的作用下显著上调。本研究的目的是研究转化生长因子 - β（TGFβ），一种存在于子宫蜕膜中的细胞因子，作为滋养层onfFN产生的刺激物的作用。我们对TGFβ重要性的初步认识源于偶然使用一名患有严重同种免疫性血小板减少症新生儿的脐带血清。在含有这种血清的培养基中培养的滋养层细胞经历了正常的形态分化，但产生的onfFN明显减少。同样，在与抗TGFβ中和抗体预孵育的正常血清中培养的滋养层细胞也产生明显较少的onfFN。外源性添加的TGFβ1在含有血小板减少血清的培养基中使滋养层细胞产生onfFN的能力恢复了4至5倍。在源自人或牛血浆的无血小板血清中，TGFβ1也诱导onfFN合成，这在条件培养基中以及通过对细胞相关ECM纤维中的onfFN进行免疫细胞化学定位来测定。剂量反应分析表明，onfFN刺激反应对TGFβ敏感，ED50为0.1 - 0.2 ng/ml。相反，TGFβ抑制β-hCG分泌3至4倍。我们的结果表明，TGFβ是滋养层onfFN产生的重要刺激物。此外，TGFβ似乎通过上调锚定滋养层标志物（onfFN）的表达和下调绒毛合体滋养层的表型标志物（hCGβ）来调节滋养层分化。我们推测，在植入环境中滋养层对TGFβ的反应性通过刺激滋养层来源的植入部位纤连蛋白的产生而有助于滋养层黏附。
