Baczyk D, Dunk C, Huppertz B, Maxwell C, Reister F, Giannoulias D, Kingdom J C P
Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada.
Placenta. 2006 Apr-May;27(4-5):367-74. doi: 10.1016/j.placenta.2005.03.006. Epub 2005 Jun 13.
Murine trophoblast stem (TS) cells express fibroblast growth factor receptor 2 (FGFR2) and are maintained in their proliferative state by fibroblast growth factor 4 (FGF4). We show in this report that in the first trimester human placenta FGFR2 expression is similarly found in a subset of villous cytotrophoblast and in proximal anchoring columns. Western analysis demonstrated declining FGFR2 protein expression as gestation advanced, suggesting a similar role for FGF in early human trophoblast proliferation. Mouse TS cell differentiation is known to occur along two distinct transcriptionally-regulated pathways; extravillous trophoblast (EVT) cells invade the uterine wall to promote maternal blood flow whilst syncytiotrophoblast lines chorionic villi in the labyrinth. Similar differentiation steps occur in the human placenta though the fate of human trophoblast stem cells is presently unknown. To investigate the mechanisms underlying human cytotrophoblast differentiation we have developed a novel cultured floating first trimester villous explant model in which denuded first trimester villi spontaneously regenerate syncytiotrophoblast following 48 h of culture. Addition of FGF4 and heparin inhibited syncytiotrophoblast regeneration in favor of forming clumps of cytotrophoblast. Proximal cells in these clumps were FGFR2 immuno-reactive and proliferative, intermediate parts expressed alpha5beta1-integrin, while the distal portion expressed HLA-G and the invasive integrin alpha1beta1 indicating differentiation to the EVT phenotype. In contrast, non-denuded villi exposed to FGF4 exhibited similar proliferation of the cytotrophoblast; however, these cells did not express any of the invasive EVT markers. We conclude that FGFR2-positive chorionic cytotrophoblasts exhibit bi-potential behaviour, being capable of forming either syncytiotrophoblast or EVT. We suggest bipotential trophoblast progenitor cells persist during first trimester human placental development.
小鼠滋养层干细胞（TS）表达成纤维细胞生长因子受体2（FGFR2），并通过成纤维细胞生长因子4（FGF4）维持其增殖状态。我们在本报告中表明，在孕早期人胎盘中，FGFR2表达同样存在于绒毛细胞滋养层的一个亚群和近端固定柱中。蛋白质印迹分析表明，随着妊娠进展，FGFR2蛋白表达下降，提示FGF在早期人滋养层细胞增殖中具有类似作用。已知小鼠TS细胞沿着两条不同的转录调控途径发生分化；绒毛外滋养层（EVT）细胞侵入子宫壁以促进母体血流，而合体滋养层则排列在迷路中的绒毛膜绒毛上。人胎盘中也发生类似的分化步骤，尽管目前人滋养层干细胞的命运尚不清楚。为了研究人细胞滋养层分化的潜在机制，我们开发了一种新型的培养漂浮孕早期绒毛外植体模型，其中裸露的孕早期绒毛在培养48小时后自发再生合体滋养层。添加FGF4和肝素可抑制合体滋养层再生，有利于形成细胞滋养层团块。这些团块中的近端细胞对FGFR2免疫反应且具有增殖性，中间部分表达α5β1整合素，而远端部分表达HLA - G和侵袭性整合素α1β1，表明分化为EVT表型。相比之下，暴露于FGF4的未裸露绒毛表现出类似的细胞滋养层增殖；然而，这些细胞不表达任何侵袭性EVT标志物。我们得出结论，FGFR2阳性的绒毛膜细胞滋养层表现出双潜能行为，能够形成合体滋养层或EVT。我们认为双潜能滋养层祖细胞在孕早期人胎盘发育过程中持续存在。
