The Immunology of Syncytialized Trophoblast

Abstract

Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved in trophoblast cell–cell fusion (aka syncytialization). Here we will review and summarize several of the mechanisms that support healthy maternal–fetal immune interactions specifically at syncytiotrophoblast interfaces.

Single Nucleus RNA Sequence (snRNAseq) Analysis of the Spectrum of Trophoblast Lineages Generated From Human Pluripotent Stem Cells in vitro

“…Both VTCN1 and CD274 bind to receptors on lymphocytes. In cancer cells and possibly in TB they are considered regulators of immune tolerance ( Holets et al, 2006 ; Schust et al, 2021 ).…”

Decreased Expression of Cytotoxic Proteins in Decidual CD8+ T Cells in Preeclampsia

“…Decidua is a place of great immune importance. It is the site of direct contact of trophoblasts with maternal immunocompetent cells [10][11][12]. Immune cells that inhabit the decidua not only maintain placental function, but control trophoblast invasion, prevent fetal rejection, and participate in defense against infections during pregnancy [13,14].…”

Development of properly-polarized trophoblast stem cell-derived organoids to model early human pregnancy

“…However, each of the reported trophoblast organoid models to date poorly recapitulates the anatomy of the developing primitive and villous human placenta, each of which is covered by a leading edge of implanting embryo or villous surface in placenta of multinucleated syncytialized trophoblast. This STB layer has several functions, including serving as: 1) the major transporting epithelium in the placenta, with capacity for polarized gas and nutrient transfer [42], 2) a physical and immunologically-active barrier to fetal infection and toxin exposures, and 3) an induction site for immunotolerance of the antigenically foreign fetus in normal pregnancies [43,44] through the shedding syncytial nuclear aggregates and exosomes that interact with the maternal immune system. Here we present an improved trophoblast organoid model derived from hTSC in the absence of forskolin exposure that presents its multinuclear layer at the outer surface of the organoids, more closely mimicking the in vivo architecture of the implanting embryo and villous placenta than prior models.…”