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Cytotrophoblast extracellular vesicles promote maternal adaptation to pregnancy

  • Author(s): Taylor, Sara Kristine
  • Advisor(s): Fisher, Susan J
  • et al.
Abstract

Pregnancy requires integration between the embryo/fetus and the mother. The placenta promotes maternal adaptations to meet the physiologic, immunologic, and metabolic demands of the developing offspring. To mediate these changes, the placenta releases large quantities of extracellular vesicles (EVs) that facilitate communication between the embryo/fetus and the mother. Few studies have investigated the contents and functions of EVs from primary cytotrophoblasts (CTBs) at midgestation. In this study, I isolated EVs from second trimester CTBs by differential ultracentrifugation and characterized them by transmission electron microscopy, immunoblotting, and mass spectrometry. The 100,000 x g pellet was enriched for vesicles with a cup-like morphology typical of exosomes. They expressed the exosomal markers CD9 and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), and the trophoblast proteins placental alkaline phosphatase (PLAP) and HLA-G. Mass spectrometry showed that the placental EVs contained proteins with roles in localization, transport, and immune functions. A cytokine array revealed that the CTB 100,000 x g pellet contained a significant amount of TNF-a. In terms of functions in local tissues, CTB EVs increased decidual stromal cell (dESF) transcription and secretion of NF-kB targets, including IL-8 as measured by qRT-PCR and cytokine array. A soluble form of the TNF-a receptor inhibited the ability of CTB 100,000 x g EVs to increase dESF secretion of IL-8. Together, the data suggest that CTB EVs enhance decidual cell release of inflammatory cytokines, which I theorize is an important component of successful pregnancy. In terms of distant sites, CTB 100,000 x g EVs promoted pancreatic b-cell proliferation and insulin production both in vivo and in vitro. Ultimately, this work identified CTB EVs as drivers of maternal adaptation to pregnancy in local and distant tissues and creates a foundation to investigate functions of these vesicles in other tissues and in the context of pregnancy complications.

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