Li Yingchun, Moretto-Zita Matteo, Leon-Garcia Sandra, Parast Mana M
Department of Pathology, University of California San Diego, La Jolla, California; Department of Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
Department of Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California; Department of Reproductive Medicine, University of California San Diego, La Jolla, California.
Am J Pathol. 2014 Dec;184(12):3332-43. doi: 10.1016/j.ajpath.2014.08.006. Epub 2014 Oct 7.
Proper differentiation of placental epithelial cells, called trophoblast, is required for implantation. Early during placentation, trophoblast cell columns help anchor the developing embryo in the uterine wall. Although proximally continuous with villous cytotrophoblast (CTB) distally, these cells differentiate into invasive extravillous trophoblast. We previously reported that p63, a p53 family member, is highly expressed in proliferative villous CTB and required for induction of the trophoblast lineage in human pluripotent stem cells. We now further explore its function in human trophoblast by using both primary CTB from the early placenta and established trophoblast cell lines. We show that p63 is expressed in epidermal growth factor receptor-positive CTB and that its expression decreases with differentiation into HLA-G(+) extravillous trophoblast. In trophoblast cell lines, p63 is expressed in JEG3 cells but absent from HTR8 cells. Overexpression of p63 in both cell lines enhances cell proliferation and significantly reduces cell migration; conversely, down-regulation of p63 in JEG3 cells reduces cell proliferation and restores cell migration. Analysis of epithelial-to-mesenchymal transition, cell adhesion, and matrix degradation pathways shows that p63 blocks epithelial-to-mesenchymal transition, promotes a CTB-specific cell adhesion profile, and inhibits expression of matrix metalloproteinases. Taken together, these data show that p63 maintains the proliferative CTB state, at least partially through regulation of epithelial-to-mesenchymal transition, cell adhesion, and matrix degradation pathways.
胎盘上皮细胞（称为滋养层细胞）的正常分化是着床所必需的。在胎盘形成的早期，滋养层细胞柱有助于将发育中的胚胎锚定在子宫壁上。尽管这些细胞近端与绒毛细胞滋养层（CTB）连续，远端却分化为侵袭性的绒毛外滋养层细胞。我们之前报道过，p53家族成员p63在增殖性绒毛CTB中高表达，并且是诱导人多能干细胞中滋养层细胞谱系所必需的。现在我们通过使用早期胎盘的原代CTB和已建立的滋养层细胞系，进一步探索其在人滋养层细胞中的功能。我们发现p63在表皮生长因子受体阳性的CTB中表达，并且随着其分化为HLA - G(+)绒毛外滋养层细胞，其表达会降低。在滋养层细胞系中，p63在JEG3细胞中表达，但在HTR8细胞中不存在。在这两种细胞系中过表达p63会增强细胞增殖并显著降低细胞迁移；相反，在JEG3细胞中下调p63会降低细胞增殖并恢复细胞迁移。对上皮 - 间质转化、细胞黏附和基质降解途径的分析表明，p63可阻断上皮 - 间质转化，促进CTB特异性的细胞黏附特征，并抑制基质金属蛋白酶的表达。综上所述，这些数据表明p63至少部分通过调节上皮 - 间质转化、细胞黏附和基质降解途径来维持增殖性CTB状态。
