The placenta is a fetal-derived transient organ critical for pregnancy and fetal development. During gestation, this organ is responsible for implantation into the maternal uterus as well as facilitating gas and nutrient exchange between the mother and fetus. Defects in placental development result in pregnancy complications such as preeclampsia and intrauterine growth restriction (IUGR). The damage done by these defects can last beyond pregnancy. Not only will placental defects compromise the health of mother and fetus during gestation but will also predispose infants to adult-onset diseases such as diabetes, obesity, and cardiovascular disease.
Sirtuin1 (SIRT1) is a NAD-dependent protein deacetylase expressed in an array of tissues and implicated in many different disease models. It regulates a variety of cellular processes such as apoptosis, inflammation, and differentiation, through deacetylation of specific proteins. Sirt1 is considered a key metabolic sensor and is therefore often implicated in metabolic diseases such as diabetes and obesity. Homozygous Sirt1-null mice have previously been reported to be growth restricted. However, though Sirt1 has been implicated in pregnancy, it has never been studied specifically in placental development and trophoblast differentiation.
For my dissertation, I explored the role of Sirt1 in mouse trophoblast differentiation and placental development. Using Sirt1-null mice, I found that in the absence of Sirt1, embryos die at e13.5 and placentas are consistently smaller. Upon investigation of the null placentas, I observed defects in both the labyrinthine layer and the junctional zone. Differentiation of wild-type and Sirt1-null trophoblast stem (TS) cells showed that, in the absence of Sirt1, TS cells fail to terminally differentiate and instead are halted in an Epcam+ labyrinthine trophoblast progenitor state. This defect is due, at least in part, to dysregulation of c-Met signaling. These findings elucidate a new role for Sirt1 during trophoblast differentiation, and indicate a potential pathway through which abnormal placental development can contribute to fetal growth restriction.