Multiple pathologies of the placenta, such as a preeclampsia and abnormally invasive placentas, are correlated with defects in trophoblast cell motility and invasion. These defects are postulated to originate during early pregnancy; however, owing to the difficulty of obtaining first trimester placental tissue, the molecular mechanisms that regulate human trophoblast cell identity and function in vivo remain poorly understood. Now, in this issue, two groups identify novel markers of human trophoblast cells and provide data to support their role in differentiation in vitro, and in trophoblast invasiveness and the etiology of preeclampsia in vivo.

Hongmei Wang, Wenxiang Meng and colleagues (dev148932) studied the expression of placenta-specific protein 8 (PLAC8), a highly conserved protein with important roles in cell differentiation, apoptosis and tumorigenesis. The authors show that, in human placenta, expression of PLAC8 is largely confined to the subpopulation of extravillous cytotrophoblasts (EVTs) that reside in the interstitial rather than the endovascular compartment. In vitro studies reveal that PLAC8 is both induced and required during the differentiation of cytotrophoblast cells into interstitial EVTs. Interestingly, forced expression of PLAC8 promotes cell invasion and migration, which is consistent with the role of interstitial EVTs in migrating and invading into the maternal decidua. Finally, the authors report a substantially elevated expression of PLAC8 in the interstitial EVT population in pregnancies complicated by severe preeclampsia.

Louise C. Laurent, Mana Parast and colleagues (dev156273) use complementary approaches to compare the molecular profile of mouse and human placenta development at multiple stages of gestation. In situ hybridisation reveals that the first trimester human placenta does not express EOMES – an important regulator of mouse trophoblast stem cells – though other regulators of murine trophoblast stem cells, CDX2 and ELF5, are expressed. In order to gain a more global view of the differences in placenta development between mouse and human, the authors perform microarray analyses on tissue spanning almost the entire gestational period: from four weeks to full-term in humans and from E7.5 to E18.5 in mouse. The authors report a large number of species-specific transcription factors and identify VGLL1 as a human-specific marker of early cytotrophoblast cells, showing that its expression is modulated in an in vitro model of human cytotrophoblast differentiation.

Taken together, these papers provide new molecular tools for investigating human placenta development and bring insight to the early events in trophoblast cell differentiation that may have implications for pregnancy-related pathologies.