Placental Accreta Spectrum: Upregulated Cytotrophoblast DOCK4 Contributes to Over Invasion

In humans, a subset of placental cytotrophoblasts (CTBs) invades the uterus and its vasculature, anchoring the pregnancy and ensuring adequate blood flow to the fetus. Appropriate depth is critical. Shallow invasion increases the risk of pregnancy complications, e.g., severe preeclampsia. Overly deep invasion, the hallmark of placenta accreta spectrum (PAS), increases the risk of pre-term delivery, hemorrhage and death. Previously a rare condition, the incidence of PAS has increased to 1:731 pregnancies, likely due to the rise in uterine surgeries (e.g., Cesarean sections). CTBs track along the scars deep into the myometrium and beyond. Here we compared the global gene expression patterns of CTBs from PAS cases to gestational age-matched control cells that invaded to the normal depth from preterm birth (PTB) deliveries. The mRNA encoding the guanine nucleotide exchange factor, DOCK4, mutations of which promote cancer cell invasion and angiogenesis, was the most highly differentially expressed molecule in PAS samples. Over-expression of DOCK4 increased CTB invasiveness, consistent with the PAS phenotype. Also, this analysis identified other genes with significantly altered expression in this disorder, potential biomarkers. These data suggest that CTBs from PAS cases up regulate a cancer-like pro-invasion mechanism, suggesting molecular as well as phenotypic similarities in the two pathologies. Expression profiling of placental cytotrophoblasts from PAS patients and healthy controls.

在人体中，一部分胎盘细胞滋养层细胞（placental cytotrophoblasts, CTBs）会侵袭子宫及其脉管系统，以此锚定妊娠并确保胎儿获得充足的血液供应。适宜的侵袭深度至关重要：侵袭过浅会增加妊娠并发症风险，例如重度子痫前期；而侵袭过深则是胎盘植入性疾病谱（placenta accreta spectrum, PAS）的典型特征，会提升早产、大出血乃至死亡的风险。
过去胎盘植入性疾病谱属于罕见病症，但其发病率现已升至每731次妊娠中就有1例，这一变化大概率与子宫手术（如剖宫产术）的增多有关。细胞滋养层细胞会顺着瘢痕组织深入子宫肌层乃至更远部位。本研究对比了胎盘植入性疾病谱患者的细胞滋养层细胞，与取自早产（preterm birth, PTB）分娩、侵袭深度符合正常范围的孕龄匹配对照细胞的全基因表达谱。
结果显示，编码鸟苷酸交换因子的DOCK4信使RNA，其突变可促进癌细胞侵袭与血管生成，是胎盘植入性疾病谱样本中差异表达程度最高的分子。对DOCK4进行过表达可增强细胞滋养层细胞的侵袭能力，这与胎盘植入性疾病谱的表型特征相符。此外，本分析还鉴定出该病症中其他表达存在显著改变的基因，这些基因均可作为潜在生物标志物。
本研究数据表明，胎盘植入性疾病谱患者的细胞滋养层细胞上调了类似癌症的促侵袭通路，提示两种病症在分子层面与表型层面均存在相似性。本数据集为胎盘植入性疾病谱患者与健康对照者的胎盘细胞滋养层细胞表达谱数据。