Third-trimester trophoblast stem cell function is impaired in fetal growth restriction

Trophoblasts are epithelial cells critical for placental development and function, ensuring healthy fetal growth. We have previously isolated trophoblast stem cells (TSC) from first trimester placentae using the side-population technique, showing that they persist to term for the first time, and are depleted in fetal growth restriction (FGR) - a serious condition of pregnancy where placental exchange function is impaired. However, the functional role of TSC in pregnancy pathologies has not previously been directly examined. Here, we first demonstrate that third-trimester side-population trophoblasts represent a TSC population that can differentiate into mature trophoblast lineages in a similar manner to their first trimester counterparts, and then combine transcriptomic and functional studies to demonstrate deficits in proliferation, differentiation, and susceptibility to cell death in FGR. Together, such stem cell level defects may have profound impacts on all downstream trophoblast lineages, potentially explaining why placentation is impaired in FGR.