Maintaining the integrity of trophoblast during growth of the placenta. Focus on "Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta".

MATERNAL-FETAL EXCHANGE OF nutrients and respiratory gases occurs across the brush border of the trophoblast lining the intervillous space of the placenta. The trophoblast is syncytial in nature and has a high rate of turnover. Therefore syncytiotrophoblast is continually replenished from an underlying layer of proliferating stem cells, the villous cytotrophoblasts, often referred to as Langhan’s layer (Fig. 1). Syncytiotrophoblast nuclei undergo programmed cell death, and there is strong evidence that the apoptotic cascade is initiated in the villous cytotrophoblast (10, 11). The apoptotic nuclei accumulate near the surface in the “syncytial knots” that are a characteristic of human placenta. From here, they are shed into the maternal circulation. They make a sizeable contribution to the cellular debris of fetal origin that is responsible for the systemic inflammatory response to pregnancy (17). While such a response occurs in normal gestation, it is greatly enhanced in preeclampsia, an endothelial disorder that is a common and potentially dangerous complication of pregnancy. Thus an advance in our comprehension of how these processes are regulated contributes to our understanding both of trophoblast biology and of the causes underlying a major pregnancy disorder. It now appears (5) that trophoblast turnover is regulated, at least in part, by the insulin-like growth factor system. Insulin-like growth factors I (IGF-I) and II (IGF-II) and their receptors are known to be important for fetal and placental growth (4). They are structurally related to insulin and can bind to insulin receptors. However, most of their effects are exerted through the IGF type 1 receptor (IGF1R). Interaction between the growth factors and their receptors is modulated by a family of six high-affinity binding proteins (IGFBP-1 through -6). Most of the components of this system are expressed at the RNA and protein level in human placenta (8). In addition, IGF-I is synthesized by the liver in response to pituitary and placental growth hormones and circulates in maternal blood together with IGFBPs. Finally, both IGF-I and IGF-II are found in fetal blood, and the binding proteins, especially IGFBP-1, are synthesized by fetal liver (9) and the uterine decidua (13). While it is clear that birth weight and placental weight are positively correlated with cord blood levels of IGF-I and IGF-II (6, 16), relatively little is known about how the IGF system affects growth of the human placenta. Hitherto, the focus has been on the expression of IGF-II on the extravillous trophoblast that invades the uterine wall and the expression of IGFBP-1 and IGFBP-4 on decidual cells (7, 8, 12). Interaction between IGF-II and IGFBPs at the maternal-fetal interface has been allotted an important role in limiting trophoblast invasion, including the subsequent migration of trophoblast to uterine spiral arteries. Thus it has been suggested that an imbalance in the IGF system leads to restriction of placental and fetal growth through restraining trophoblast invasion and decreasing placental blood flow. In this view, reduced growth of villous trophoblast is seen as secondary to the reduced supply of oxygen and nutrients. Now a well-designed and carefully executed study by Forbes et al. (5) using first-trimester villous explants convincingly demonstrates a direct effect of the IGF system on trophoblast turnover in human placenta. IGF-I and -II enhanced cytotrophoblast proliferation and syncytium formation and reduced cytotrophoblast apoptosis, suggesting a key role for the IGF system in maintaining the maternal-facing syncytiotrophoblast layer of the placenta. Importantly, IGF applied to this surface, mimicking exposure to maternal IGF-I in the intervillous space, was able to influence proliferation in the underlying cytotrophoblast layer. The effects on proliferation and syncytium formation were shown to be mediated by the MAPK pathway, whereas the effects on survival depended on the phosphoinositide 3-kinase/Akt pathway (5). It is well established that these pathways are activated by binding of IGFs to IGF1R (3), which is expressed on the microvillous membrane of syncytiotrophoblast. This new study clearly demonstrates the advantage of using villous explants, in which the contact between cellular and syncytial trophoblast is maintained. The two layers are conAddress for reprint requests and other correspondence: A. M. Carter, Physiology and Pharmacology, Univ. of Southern Denmark, Winsloewvej 21, DK-5000 Odense, Denmark (e-mail: [email protected]). Fig. 1. Stylized cross section of a placental villus to show trophoblast turnover in the human placenta. Maternal blood circulates in the intervillous space. Transfer of nutrients and respiratory gases toward fetal capillaries (fetal cap) occurs across an outer layer of syncytiotrophoblast (syn troph). It is constantly replenished from a discontinuous layer of stem cells, the villous cytotrophoblasts (cyt troph). Even before fusion, the nuclei committed to the syncytiotrophoblast are programmed for cell death. Apoptotic nuclei from the aging syncytiotrophoblast accumulate in “syncytial knots” that eventually are shed into the maternal blood stream. Trophoblast turnover and renewal are tightly regulated, and it is now apparent that insulin-like growth factors play a key role in this process. Am J Physiol Cell Physiol 294: C1303–C1304, 2008; doi:10.1152/ajpcell.00149.2008.