Chen Chie-Pein, Chen Chen-Yu, Chen Chia-Yu, Kuo Yi-Hsiu, Chen Hungwen
Division of High Risk Pregnancy, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
Division of High Risk Pregnancy, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
Placenta. 2025 Jun 26;167:71-79. doi: 10.1016/j.placenta.2025.04.028. Epub 2025 May 1.
To study whether the upregulation of HtrA4 expression in extravillous trophoblasts and the downregulation of HtrA1 expression in defective deciduae underlined the mechanisms of placenta accreta spectrum (PAS) development.
Tissue samples from patients undergone cesarean hysterectomy because of postpartum hemorrhage due to PAS (n = 15) or uterine atony (control group; n = 10) were analyzed through immunostainings. The effect of extracellular matrix (ECM) on trophoblast HtrA4 expression, and HtrA4 in the alteration of trophoblast epithelial-to-mesenchymal transition, proliferation, invasion and HtrA1 inhibition were assessed.
ECM molecule collagen I, collagen IV, fibronectin, or laminin were highly expressed in decidua and myometrium. Culturing trophoblasts with these molecules induced HtrA4 expression. HtrA4 upregulated the expression of N-cadherin, vimentin, integrin β1, snail, and matrix metalloproteinase-2 but downregulated that of zonula occludens-1. HtrA4 knockdown inhibited these effects. HtrA4 knockdown or pretreatment with recombinant HtrA1 inhibited HtrA4-induced trophoblast invasion. HtrA4 promoted trophoblast proliferation. Numerous extravillous trophoblasts exhibiting strong HtrA4 expression invaded the myometrium at the villous adherence sites affected by PAS. Relatively few extravillous trophoblasts were observed at the nonadherence sites and in the control specimens; these trophoblasts exhibited weak or no HtrA4 expression. HtrA1 was primarily expressed over the decidua.
ECM in decidua and myometrium induced trophoblast HtrA4 expression. Decidual HtrA1 inhibited HtrA4-induced trophoblast invasion. Without the inhibition of HtrA1, HtrA4 expression and invasion was upregulated in the trophoblasts of patients with PAS. The reciprocal effects of HtrA4 and HtrA1 at the maternal-fetal interface may be involved in the pathogenesis of PAS.
研究绒毛外滋养层细胞中HtrA4表达上调以及蜕膜缺陷中HtrA1表达下调是否是胎盘植入谱系（PAS）发生发展的潜在机制。
通过免疫染色分析因PAS产后出血行剖宫产子宫切除术患者（n = 15）或子宫收缩乏力患者（对照组；n = 10）的组织样本。评估细胞外基质（ECM）对滋养层细胞HtrA4表达及HtrA4在滋养层上皮-间质转化、增殖、侵袭改变和HtrA1抑制中的作用。
ECM分子Ⅰ型胶原、Ⅳ型胶原、纤连蛋白或层粘连蛋白在蜕膜和子宫肌层中高表达。用这些分子培养滋养层细胞可诱导HtrA4表达。HtrA4上调N-钙黏蛋白、波形蛋白、整合素β1、蜗牛蛋白和基质金属蛋白酶-2的表达，但下调紧密连接蛋白-1的表达。敲低HtrA4可抑制这些作用。敲低HtrA4或用重组HtrA1预处理可抑制HtrA4诱导的滋养层细胞侵袭。HtrA4促进滋养层细胞增殖。在受PAS影响的绒毛附着部位，大量强表达HtrA4的绒毛外滋养层细胞侵入子宫肌层。在非附着部位和对照样本中观察到的绒毛外滋养层细胞相对较少；这些滋养层细胞HtrA4表达较弱或无表达。HtrA1主要在蜕膜上表达。
蜕膜和子宫肌层中的ECM诱导滋养层细胞HtrA4表达。蜕膜HtrA1抑制HtrA4诱导的滋养层细胞侵袭。在没有HtrA1抑制的情况下，PAS患者滋养层细胞中HtrA4表达和侵袭上调。HtrA4和HtrA1在母胎界面的相互作用可能参与了PAS的发病机制。
