NOTUM-mediated WNT silencing drives extravillous trophoblast cell lineage development.

Trophoblast stem (TS) cells have the unique capacity to differentiate into specialized cell types, including extravillous trophoblast (EVT) cells. EVT cells invade into and transform the uterus where they act to remodel the vasculature facilitating the redirection of maternal nutrients to the developing fetus. Disruptions in EVT cell development and function are at the core of pregnancy-related disease.

Leveraging chorionic villus biopsies for the derivation of patient-specific trophoblast stem cells.

Human trophoblast stem () cells are an informative in vitro model for the generation and testing of biologically meaningful hypotheses. The goal of this project was to derive patient-specific TS cell lines from clinically available chorionic villus sampling biopsies. Cell outgrowths were captured from human chorionic villus tissue specimens cultured in modified human TS cell medium.

NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT.

Trophoblast stem () cells have the unique capacity to differentiate into specialized cell types, including extravillous trophoblast () cells. EVT cells invade into and transform the uterus where they act to remodel the vasculature facilitating the redirection of maternal nutrients to the developing fetus. Disruptions in EVT cell development and function are at the core of pregnancy-related disease.

Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape.

The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells.

CITED2 is a conserved regulator of the uterine-placental interface.

Establishment of the hemochorial uterine-placental interface requires exodus of trophoblast cells from the placenta and their transformative actions on the uterus, which represent processes critical for a successful pregnancy, but are poorly understood. We examined the involvement of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) in rat and human trophoblast cell development. The rat and human exhibit deep hemochorial placentation.

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).

Paradigms for investigating invasive trophoblast cell development and contributions to uterine spiral artery remodeling.

Uterine spiral arteries are extensively remodeled during placentation to ensure sufficient delivery of maternal blood to the developing fetus. Uterine spiral arterial remodeling is complex, as cells originating from both mother and developing conceptus interact at the maternal interface to regulate the extracellular matrix remodeling and vasculature restructuring necessary for successful placentation. Despite this complexity, one mechanism critical to spiral artery remodeling is trophoblast cell invasion into the maternal compartment.

ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development.

Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development.

Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity.

Introduction: The hemochorial placenta provides a critical barrier at the maternal-fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by diabetes mellitus; however, the effects of poorly controlled diabetes on placental formation, and subsequently fetal development, are not fully understood.

Research Design And Methods: Streptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of poorly controlled diabetes on placental formation and fetal development.

Transgelin induces dysfunction of fetal endothelial colony-forming cells from gestational diabetic pregnancies.

Fetal exposure to gestational diabetes mellitus (GDM) predisposes children to future health complications including hypertension and cardiovascular disease. A key mechanism by which these complications occur is through the functional impairment of vascular progenitor cells, including endothelial colony-forming cells (ECFCs). Previously, we showed that fetal ECFCs exposed to GDM have decreased vasculogenic potential and altered gene expression.

Hemochorial placentation: development, function, and adaptations.

Placentation is a reproductive adaptation that permits fetal growth and development within the protected confines of the female reproductive tract. Through this important role, the placenta also determines postnatal health and susceptibility to disease. The hemochorial placenta is a prominent feature in primate and rodent development.

Kinetic Analysis of Vasculogenesis Quantifies Dynamics of Vasculogenesis and Angiogenesis In Vitro.

Vasculogenesis is a complex process by which endothelial stem and progenitor cells undergo de novo vessel formation. Quantitative assessment of vasculogenesis has become a central readout of endothelial progenitor cell functionality, and therefore, several attempts have been made to improve both in vitro and in vivo vasculogenesis models. However, standard methods are limited in scope, with static measurements failing to capture many aspects of this highly dynamic process.

Kinetic analyses of vasculogenesis inform mechanistic studies.

Vasculogenesis is a complex process by which endothelial stem and progenitor cells undergo de novo vessel formation. Quantitative assessment of vasculogenesis is a central readout of endothelial progenitor cell functionality. However, current assays lack kinetic measurements.

Mesenchyme Homeobox 2 Enhances Migration of Endothelial Colony Forming Cells Exposed to Intrauterine Diabetes Mellitus.

Diabetes mellitus (DM) during pregnancy has long-lasting implications for the fetus, including cardiovascular morbidity. Previously, we showed that endothelial colony forming cells (ECFCs) from DM human pregnancies have decreased vasculogenic potential. Here, we evaluate whether the molecular mechanism responsible for this phenotype involves the transcription factor, Mesenchyme Homeobox 2 (MEOX2).

Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.

Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM-exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression.