Intersection of regulatory pathways controlling hemostasis and hemochorial placentation.
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 TFPI loss-of-function rat 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.
Proceedings of the National Academy of Sciences of the United States of America
hemostasis; placenta; trophoblast cell; uterine spiral artery
Muto M, Chakraborty D, Varberg KM, Moreno-Irusta A, Iqbal K, Scott RL, McNally RP, Choudhury RH, Aplin JD, Okae H, Arima T, Matsumoto S, Ema M, Mast AE, Grundberg E, Soares MJ. Intersection of regulatory pathways controlling hemostasis and hemochorial placentation. Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2111267118. doi: 10.1073/pnas.2111267118. PMID: 34876522.