Hess A P, Hamilton A E, Talbi S, Dosiou C, Nyegaard M, Nayak N, Genbecev-Krtolica O, Mavrogianis P, Ferrer K, Kruessel J, Fazleabas A T, Fisher S J, Giudice L C
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0132, USA.
Biol Reprod. 2007 Jan;76(1):102-17. doi: 10.1095/biolreprod.106.054791. Epub 2006 Oct 4.
During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54,600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.
在植入的侵袭期，滋养层细胞和母体蜕膜基质细胞分泌调节滋养层细胞分化并使其迁移至母体子宫内膜的产物。绒毛外滋养层细胞与母体蜕膜之间的旁分泌相互作用对于胚胎成功植入至关重要，包括建立胎盘血管系统、将胎盘锚定至子宫壁以及促进对胎儿异体移植物的免疫接受。据我们所知，滋养层细胞与蜕膜之间的整体相互作用至今尚未阐明，本研究采用功能基因组学方法来研究这些旁分泌相互作用。用人孕酮使人类子宫内膜基质细胞蜕膜化，并用来自人类滋养层细胞的条件培养基（TCM）进一步处理，或者作为对照，用来自未蜕膜化基质细胞的对照条件培养基（CCM）处理0、3和12小时。分离总RNA并进行处理，以便在包含54,600个基因的全基因组高密度寡核苷酸阵列上进行分析。我们发现，与CCM相比，基质细胞与TCM共同孵育12小时后，1374个基因显著上调，3443个基因显著下调。上调最明显的基因包括趋化因子CXCL1（GRO1）和IL8、CXCR4以及其他参与免疫反应的基因（CCL8 [SCYA8]、五聚素3（PTX3）、IL6以及干扰素调节和相关基因），以及TNFAIP6（肿瘤坏死因子α诱导蛋白6）和金属蛋白酶（MMP1、MMP10和MMP14）。下调的基因包括生长因子，如IGF1、FGF1、TGFB1和血管生成素-1，以及参与Wnt信号传导的基因（WNT4和FZD）。实时RT-PCR和ELISA以及对人胎盘床标本的免疫组织化学分析证实了上调和下调组代表性基因的这些数据。数据表明，蜕膜化的子宫内膜基质细胞对滋养层细胞分泌产物有反应，促炎细胞因子和趋化因子以及血管生成/静态因子显著诱导。数据表明，滋养层细胞的作用是改变蜕膜的局部免疫环境，以促进植入过程，并确保有丰富的细胞因子/趋化因子环境，同时在植入的侵袭期限制基质细胞的有丝分裂活性。
