Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta

Abstract

Villous trophoblast in the human placenta consists of a population of proliferating stem cells which differentiate and individually fuse into the syncytiotrophoblast. We studied the apoptotic cascade in this complex epithelial layer by immunohistochemical localization of Fas, FasL, Bcl-2, Mcl-1, pro-caspase-3 and caspase-3, T-cell-restricted intracellular antigen-related protein (TIAR), poly(ADP-ribose) polymerase (PARP), lamin B, topoisomerase IIalpha, and transglutaminase II in cryostat and paraffin-fixed tissue sections from normal human first-trimester and term placental villi. The relationship between the apoptotic cascade and syncytial fusion was studied by coincubation of intact villi with FITC-coupled annexin-V, to detect the phosphatidylserine flip, and propidium iodide, to detect plasma membrane permeability. The final events of the apoptotic cascade were studied by the TUNEL reaction and ultrastructural appearance of the trophoblast. The phosphatidylserine flip was identified in some of the villous cytotrophoblastic cells, but the presence of both Bcl-2 and Mcl-1 proteins presumably prevented continuation of the apoptotic cascade. The syncytiotrophoblast demonstrated heterogeneous findings, suggesting variable progression along the apoptotic cascade. In some areas Bcl-2 and Mcl-1 predominated, with preservation of the nuclear proteins PARP, lamin B, and topoisomerase IIalpha; in other areas, especially in and around syncytial sprouts, Bcl-2 and Mcl-1 were absent, accompanied by loss of nuclear proteins, presence of phosphatidylserine flip, and TUNEL positivity. These data suggest that the apoptotic cascade is initiated in the villous cytotrophoblast, which in turn promotes syncytial fusion. Donation of anti-apoptotic proteins into the syncytium, such as Bcl-2 and Mcl-1, focally inhibits further progression along this cascade. Completion of the apoptotic cascade takes place in and around syncytial sprouts, providing further evidence that these are the sites of trophoblast shedding into the maternal circulation.

Mitochondrial toxicity and caspase activation in HIV pregnant women

“…In uninfected pregnancies the apoptotic rate of caspase‐3 activation probably increases as a physiological mechanism to delete newborn cells from the maternal blood 45. However, this increase was significantly enhanced in HIV pregnancies in concordance with accumulated, previous NRTI exposure.…”

Maternal serum of women with pre-eclampsia reduces trophoblast cell viability: evidence for an increased sensitivity to Fas-mediated apoptosis

“…Specifically, deportation of villous trophoblast debris directly into the maternal circulation [10][11][12]15 has been implicated in the genesis of the exaggerated intravascular maternal inflammatory response noted in patients with pre-eclampsia 13,14,[16][17][18] . However, whether trophoblast debris is generated through apoptosis or necrosis has not been determined [57][58][59] . This issue is important, because the biological effects of necrotic or apoptotic trophoblast debris may be different.…”

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

“…The rate of syncytial fusion exceeds the amount that is required for villous growth; hence up to 3 g of V-CTs are shed as apoptotic material into the maternal circulation per day. 4 In the most severe forms of human placental pathology resulting in fetal death, such as severe intrauterine growth restriction (IUGR), premature placental separation (abruption) and severe preeclampsia arising before 32 weeks of gestation, defects in both pathways of trophoblast development have been observed. 5,6 These defects include poor EV-CT invasion and transformation of the spiral arteries in severe early-onset preeclampsia, 5,7 and reduced elaboration of chorionic villous trees 8,9 with reduced numbers of proliferating V-CT in severe early-onset IUGR.…”