Intersection of regulatory pathways controlling hemostasis and hemochorial placentation
Intersection of regulatory pathways controlling hemostasis and hemochorial placentation
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DOI：
10.1073/pnas.2111267118
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发表时间：
2021-12-14
影响因子：
11.1
通讯作者：
Soares，Michael J.
中科院分区：
文献类型：
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作者：
Muto，Masanaga;Chakraborty，Damayanti;Soares，Michael J.
血绒质胎盘的特点是滋养层细胞的发育，专门与子宫血管床相互作用。我们利用滋养层干（TS）细胞和突变大鼠模型来研究控制滋养层细胞发育的调控机制。 TS 细胞分化的特点是获得指示内皮细胞样表型的转录特征，其中包括组织因子途径抑制剂 (TFPI) 在内的抗凝因子的表达突出了这一点。 TFPI 定位于大鼠胎盘部位的侵袭性血管内滋养层细胞。大鼠 TS 细胞中 TFPI 的破坏会干扰内皮细胞样血管内滋养层细胞表型的发育。类似地，TFPI 在位于妊娠早期人胎盘组织内以及人 TS 细胞分化后的人侵袭性/绒毛外滋养层 (EVT) 细胞中表达。人类 TS 细胞分化为 EVT 细胞需要 TFPI。接下来我们研究了 TFPI 在胎盘部位的生理相关性。基因组编辑的全球 TFPI 功能丧失模型揭示了 TFPI 在胚胎发育中的关键作用，导致同质妊娠中期致死率，从而阻碍了对 TFPI 作为子宫内滋养层细胞侵袭的妊娠晚期波调节剂的作用的分析。体内滋养层特异性 TFPI 敲低与妊娠相容，但对子宫胎盘界面产生深远影响，包括限制子宫内滋养层细胞侵袭的深度，同时导致自然杀伤细胞积聚和纤维蛋白沉积增加。总的来说，该实验表明 TFPI 作为侵入性/EVT 细胞发育、子宫螺旋动脉重塑和母胎界面止血的保守调节剂。
Hemochorial placentation is characterized by the development of trophoblast cells specialized to interact with the uterine vascular bed. We utilized trophoblast stem (TS) cell and mutant rat models to investigate regulatory mechanisms controlling trophoblast cell development. TS cell differentiation was characterized by acquisition of transcript signatures indicative of an endothelial cell-like phenotype, which was highlighted by the expression of anticoagulation factors including tissue factor pathway inhibitor (TFPI). TFPI localized to invasive endovascular trophoblast cells of the rat placentation site. Disruption of TFPI in rat TS cells interfered with development of the endothelial cell-like endovascular trophoblast cell phenotype. Similarly, TFPI was expressed in human invasive/extravillous trophoblast (EVT) cells situated within first-trimester human placental tissues and following differentiation of human TS cells. TFPI was required for human TS cell differentiation to EVT cells. We next investigated the physiological relevance of TFPI at the placentation site. Genome-edited global TFPIloss-of-functionrat models revealed critical roles for TFPI in embryonic development, resulting in homogeneous midgestation lethality prohibiting analysis of the role of TFPI as a regulator of the late-gestation wave of intrauterine trophoblast cell invasion. In vivo trophoblast-specific TFPI knockdown was compatible with pregnancy but had profound effects at the uterine–placental interface, including restriction of the depth of intrauterine trophoblast cell invasion while leading to the accumulation of natural killer cells and increased fibrin deposition. Collectively, the experimentation implicates TFPI as a conserved regulator of invasive/EVT cell development, uterine spiral artery remodeling, and hemostasis at the maternal–fetal interface.