Abstract
Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide. The primary etiology is considered to be abnormal development and function of placental cells called trophoblasts. We previously developed a two-step protocol for differentiation of human pluripotent stem cells, first into cytotrophoblast (CTB) progenitor-like cells, and then into both syncytiotrophoblast (STB)- and extravillous trophoblast (EVT)-like cells, and showed that it can model both normal and abnormal trophoblast differentiation. We have now applied this protocol to induced pluripotent stem cells (iPSC) derived from placentas of pregnancies with or without PE. While there were no differences in CTB induction or EVT formation, PE-iPSC-derived trophoblast showed a defect in syncytialization, as well as a blunted response to hypoxia. RNAseq analysis showed defects in STB formation and response to hypoxia; however, DNA methylation changes were minimal, corresponding only to changes in response to hypoxia. Overall, PE-iPSC recapitulated multiple defects associated with placental dysfunction, including a lack of response to decreased oxygen tension. This emphasizes the importance of the maternal microenvironment in normal placentation, and highlights potential pathways that can be targeted for diagnosis or therapy, while absence of marked DNA methylation changes suggests that other regulatory mechanisms mediate these alterations.
Highlights
Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide
There are three main trophoblast cell types in the placenta; (1) cytotrophoblast (CTB), a self-renewing multipotent trophoblast progenitor cell; (2) syncytiotrophoblast (STB), which arise by cell–cell fusion of CTB in chorionic villi, and mediate nutrient/gas exchange and synthesize key pregnancy hormones; and (3) extravillous trophoblast (EVT), which arise from CTB that differentiate while migrating along the trophoblast cell column and invade the uterine wall, thereby anchoring the placenta to the uterus, while remodeling maternal spiral arteries to establish the blood supply to the feto-placental u nit[6,7]
We have shown that this protocol recapitulates normal trophoblast differentiation, but can be used to model placental disease
Summary
Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide. There are three main trophoblast cell types in the placenta; (1) cytotrophoblast (CTB), a self-renewing multipotent trophoblast progenitor cell; (2) syncytiotrophoblast (STB), which arise by cell–cell fusion of CTB in chorionic villi, and mediate nutrient/gas exchange and synthesize key pregnancy hormones; and (3) extravillous trophoblast (EVT), which arise from CTB that differentiate while migrating along the trophoblast cell column and invade the uterine wall, thereby anchoring the placenta to the uterus, while remodeling maternal spiral arteries to establish the blood supply to the feto-placental u nit[6,7] The bulk of this uterine invasion and maternal vascular remodeling takes place prior to 10 weeks gestational age, while the placenta is developing under relative hypoxia[8]. To date, investigation of the underlying molecular mechanisms of this disease has been hampered by the lack of human trophoblast cells that accurately represent the early stages of placental d evelopment[17]
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