Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
Dev Biol. 2011 Oct 1;358(1):231-9. doi: 10.1016/j.ydbio.2011.07.036. Epub 2011 Aug 4.
The placenta is composed of multiple trophoblast cell types that have diverse endocrine, vascular and nutrient transport functions. We have developed a transgenic system to investigate the developmental and functional roles of specific cell types using conditional expression of a cytotoxin to induce cell ablation in transgenic mice. The Tpbpa gene is expressed in ectoplacental cone cells starting between embryonic days (E) 7.5 and 8.5, and later in the spongiotrophoblast layer of the mature placenta. Tpbpa-positive cells are progenitors of many trophoblast subtypes including three subtypes of trophoblast giant cells (TGCs) and glycogen trophoblast cells. We used a Cre recombinase transgene driven by the Tpbpa promoter to irreversibly activate a diphtheria toxin A (DTA) transgene. Cre/DTA double transgenic placentas showed dramatic reduction of Tpbpa-positive spongiotrophoblast cells by E10.5 and conceptuses died by ~E11.5. The number of cells associated with maternal blood spaces, spiral artery TGCs (SpA-TGCs) and canal TGCs, and glycogen trophoblast cells were reduced. The loss of these specific trophoblast subtypes, especially SpA-TGCs, was correlated with a decrease in maternal spiral artery diameters, indicating a critical role of these cells in modulating the maternal vasculature. In contrast, parietal TGCs were not significantly reduced by progenitor cell ablation, suggesting that there is compensatory growth of this population and indeed a population of Ascl2 (Mash2)-positive/Tpbpa-negative cells was increased in the spongiotrophoblast layer in the Cre/DTA double transgenics. Our work demonstrates that the Tpbpa-positive lineage is essential for placental function and particularly critical for maternal vasculature remodeling.
胎盘由多种滋养层细胞类型组成，具有多种内分泌、血管和营养运输功能。我们开发了一种转基因系统，通过条件表达细胞毒素来诱导转基因小鼠中的细胞消融，从而研究特定细胞类型的发育和功能作用。Tpbpa 基因在胚胎第 7.5 天至 8.5 天之间在胎盘外细胞锥体中表达，随后在成熟胎盘的海绵滋养层中表达。Tpbpa 阳性细胞是许多滋养层亚型的祖细胞，包括三种滋养层巨细胞（TGC）和糖原滋养层细胞。我们使用 Tpbpa 启动子驱动的 Cre 重组酶转基因不可逆地激活白喉毒素 A（DTA）转基因。Cre/DTA 双转基因胎盘在 E10.5 时显示出 Tpbpa 阳性海绵滋养层细胞的急剧减少，并且胚胎在 E11.5 左右死亡。与母体血液空间相关的细胞数量、螺旋动脉 TGC（SpA-TGC）和管 TGC 以及糖原滋养层细胞减少。这些特定滋养层亚型的丧失，特别是 SpA-TGC，与母体螺旋动脉直径的减小相关，表明这些细胞在调节母体血管方面起着关键作用。相比之下，滋养层细胞的消融并没有显著减少壁细胞，这表明该细胞群存在代偿性生长，实际上，在 Cre/DTA 双转基因中，Ascl2（Mash2）阳性/Tpbpa 阴性细胞的数量增加。我们的工作表明，Tpbpa 阳性谱系对于胎盘功能至关重要，特别是对于母体血管重塑至关重要。
