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Intersection of regulatory pathways controlling hemostasis and hemochorial placentation
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- Gene Editing
Multidisciplinary
Lipoproteins
Placenta
Stem Cells
Endothelial Cells
Biological Sciences
female genital diseases and pregnancy complications
Placentation
Rats
Trophoblasts
Rats, Sprague-Dawley
Pregnancy
embryonic structures
Mutation
Animals
Humans
Female
RNA Interference
CRISPR-Cas Systems
reproductive and urinary physiology
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 118
- Issue :
- 50
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....53e518bb825f746938bcad7edf1ac7b0