Skp2 contributes to cell cycle progression in trophoblast stem cells and to placental development

Abstract

All trophoblast subtypes of the placenta are derived from trophoblast stem cells (TSCs). TSCs have the capacity to self‐renew, but how the proliferation of these cells is regulated in the undifferentiated state has been largely unclear. We now show that the F‐box protein Skp2 regulates the proliferation of TSCs and thereby plays a pivotal role in placental development in mice on the C57BL/6 background. The placenta of Skp2−/− mouse embryos on the C57BL/6 background was smaller than that of their Skp2+/+ littermates, with the mutant embryos also manifesting intrauterine growth retardation. Although the Skp2−/− mice were born alive, most of them died before postnatal day 21, presumably as a result of placental defects. Depletion of Skp2 in TSCs cultured in the undifferentiated state resulted in a reduced rate of proliferation and arrest of the cell cycle in G1 phase, indicative of a defect in self‐renewal capacity. The cell cycle arrest apparent in Skp2‐deficient TSCs was reversed by additional ablation of the cyclin‐dependent kinase inhibitor (CKI) p57 but not by that of the CKI p27. Our results thus suggest that Skp2‐mediated degradation of p57 is an important determinant of the self‐renewal capacity of TSCs during placental development, at least in mice of certain genetic backgrounds.

A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells

“…4b , and Supplementary Data 1 ) 10 , 37 . These genes included known trophoblast regulators such as ARID3A 40 , CTNNB1 8 , GATA2 31 , 41 , and SKP2 42 , as well as genes like ARID5B , TCAF1 , and TEAD1 , which have not previously been associated with trophoblast biology (Fig. 2e and Supplementary Fig.…”

Pluripotent stem cells proliferation is associated with placentation in dogs

“…Studies about stem cells presence in the uterine epithelium have been performed in humans as a source of potential cell therapies (Ono et al, 2010;Gargett et al, 2012;Yamauchi et al, 2020). Furthermore, studies with animal models show that endometrial cells have different proliferative capacity especially on the endometrial epithelium, suggesting the presence of stem cell population in this region (Chan and Gargett, 2006).…”