Placental apoptosis in health and disease

Abstract

Apoptosis, programmed cell death, is an essential feature of normal placental development but is exaggerated in association with placental disease. Placental development relies upon effective implantation and invasion of the maternal decidua by the placental trophoblast. In normal pregnancy, trophoblast apoptosis increases with placental growth and advancing gestation. However, apoptosis is notably exaggerated in the pregnancy complications, hydatidiform mole, pre-eclampsia, and intrauterine growth restriction (IUGR). Placental apoptosis may be initiated by a variety of stimuli, including hypoxia and oxidative stress. In common with other cell-types, trophoblast apoptosis follows the extrinsic or intrinsic pathways culminating in the activation of caspases. In contrast, the formation of apoptotic bodies is less clearly identified, but postulated by some to involve the clustering of apoptotic nuclei and liberation of this material into the maternal circulation. In addition to promoting a favorable maternal immune response, the release of this placental-derived material is thought to provoke the endothelial dysfunction of pre-eclampsia. Widespread apoptosis of the syncytiotrophoblast may also impair trophoblast function leading to the reduction in nutrient transport seen in IUGR. A clearer understanding of placental apoptosis and its regulation may provide new insights into placental pathologies, potentially suggesting therapeutic targets.

Fig. 1

Apoptosis in the villous placenta. (a) Light micrograph (oil immersion, H & E stained) of 4 μm section of term villous placenta. Apoptotic nuclei of trophoblast highlighted (arrows). Magnification × 1000. (b) Electron micrograph showing pyknotic and apoptotic nuclei within the syncytiotrophoblast (original magnification × 4250). Smith et al. 1997, reproduced with permission. (c) Increased DNA fragmentation (laddering) in term trophoblast under hypoxic conditions. Reproduced from Levy et al. 2000 with permission.

Fig. 2

Apoptotic multi-nucleated giant cell from the third trimester placental bed (arrow). (a) Stained for cleaved cytokeratin 18 (M30) and (b) TUNEL. Reproduced from Kadyrov et al. 2001 with permission.

Fig. 3

Exaggerated trophoblast apoptosis in pre-eclampsia. (a) occasional TUNEL positive nuclei (arrows) in the syncytiotrophoblast in normal pregnancy. (b) increased apoptotic events in pre-eclampsia (brown stained nuclei). Reproduced from Heazell et al. 2008 with permission.