Use of a human embryonic stem cell model to discover GABRP, WFDC2, VTCN1 and ACTC1 as markers of early first trimester human trophoblast
Use of a human embryonic stem cell model to discover GABRP, WFDC2, VTCN1 and ACTC1 as markers of early first trimester human trophoblast
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DOI：
10.1093/molehr/gaaa029
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发表时间：
2020-06-01
影响因子：
4
通讯作者：
Schulz, Laura C.
中科院分区：
文献类型：
--
作者：
Karvas, Rowan M.;McInturf, Samuel;Schulz, Laura C.
人类妊娠早期胎盘的发育知之甚少。许多概念在这个阶段丢失。据认为，先兆子痫，宫内生长受限和其他胎盘综合征，表现在怀孕后期可能起源于胎盘早期。因此，需要早期人类胎盘发育的模型。用BMP 4（骨形态发生蛋白4）加A83-01（ACTIVIN/NODAL信号传导抑制剂）和PD 173074（成纤维细胞生长因子2或FGF 2信号传导抑制剂）（BAP条件）处理人胚胎干细胞（hESC）诱导分化为滋养层谱系（hESC（BAP）），但尚不清楚这些细胞类似于滋养层分化的哪个阶段。在这里，比较人胚胎干细胞（BAP）的转录组的滋养层细胞从人胚泡，滋养层干细胞和胎盘收集在妊娠的第一个-第三个三个月的主成分分析表明，人胚胎干细胞8天后BAP治疗最类似于第一个三个月的合体滋养层细胞。为了进一步检验这一假设，转录本被鉴定为在人胚胎干细胞（BAP）中表达，但在从足月胎盘分离的滋养层细胞培养物中不表达。GABRP（γ-氨基丁酸A型受体亚基Pi）、WFDC 2（WAP四二硫键核心结构域2）、VTCN 1（含T细胞活化抑制剂1的V-set结构域）和ACTC 1（肌动蛋白α心肌1）四个基因编码的蛋白质在妊娠4-9周时免疫定位于胎盘，并且其表达随胎龄下降（R-2 = 0.61-0.83）。没有一个在学期中出现。表达主要定位于hESC（BAP）细胞和早孕胎盘材料的合体滋养层。WFDC 2、VTCN 1和ACTC 1以前在胎盘中未被描述。这些结果支持的假设，hESC（BAP）代表人类滋养层类似的早期妊娠，是一种工具，发现重要的因素，这一阶段的胎盘。
Human placental development during early pregnancy is poorly understood. Many conceptuses are lost at this stage. It is thought that preeclampsia, intrauterine growth restriction and other placental syndromes that manifest later in pregnancy may originate early in placentation. Thus, there is a need for models of early human placental development. Treating human embryonic stem cells (hESCs) with BMP4 (bone morphogenic protein 4) plus A83-01 (ACTIVIN/NODAL signaling inhibitor) and PD173074 (fibroblast growth factor 2 or FGF2 signaling inhibitor) (BAP conditions) induces differentiation to the trophoblast lineage (hESC(BAP)), but it is not clear which stage of trophoblast differentiation these cells resemble. Here, comparison of the hESC(BAP) transcriptome to those of trophoblasts from human blastocysts, trophoblast stem cells and placentas collected in the first-third trimester of pregnancy by principal component analysis suggests that hESC after 8 days BAP treatment most resemble first trimester syncytiotrophoblasts. To further test this hypothesis, transcripts were identified that are expressed in hESC(BAP) but not in cultures of trophoblasts isolated from term placentas. Proteins encoded by four genes, GABRP (gamma-aminobutyric acid type A receptor subunit Pi), WFDC2 (WAP four-disulfide core domain 2), VTCN1 (V-set domain containing T-cell activation inhibitor 1) and ACTC1 (actin alpha cardiac muscle 1), immunolocalized to placentas at 4-9 weeks gestation, and their expression declined with gestational age (R-2 = 0.61-0.83). None are present at term. Expression was largely localized to syncytiotrophoblast of both hESC(BAP) cells and placental material from early pregnancy. WFDC2, VTCN1 and ACTC1 have not previously been described in placenta. These results support the hypothesis that hESC(BAP) represent human trophoblast analogous to that of early first trimester and are a tool for discovery of factors important to this stage of placentation.