Side-Population Trophoblasts Exhibit the Differentiation Potential of a Trophoblast Stem Cell Population, Persist to Term, and are Reduced in Fetal Growth Restriction

Abstract

Background: Fetal growth restriction often results from poor placental function and is a major cause of stillbirth. Clinically, fetal growth restriction is difficult to diagnose and currently has no effective treatment. Trophoblasts are unique placental cells that form the feto-maternal interface and facilitate nutrient and gas exchange. Fetal growth restriction is linked to inadequate trophoblast function. However, our understanding of the mechanisms underlying this dysfunction are poor, in part because of our inability to isolate and study the trophoblast stem cells from which mature trophoblasts arise in pathologic pregnancies.

Methods: Cells isolated from first-trimester placentae using the Hoechst side-population technique were propagated or differentiated into mature trophoblasts. Side-population trophoblasts were isolated from normal third-trimester and growth restricted placentae using the same technique. First and third-trimester side-population trophoblasts were compared by microarray analysis.

Results: First-trimester side-population trophoblasts could be propagated in an undifferentiated state or differentiated, via intermediate cytotrophoblasts, into syncytiotrophoblast or extravillous trophoblasts. Using the same technique, side-population trophoblasts could be isolated from term placentae for the first time, demonstrating that while they were present at consistent levels throughout gestation (~3·5%), side-population trophoblasts were significantly depleted in growth restricted pregnancies (0·32%).

Conclusions: Our novel method of isolating a population of human trophoblast stem cell-like cells directly from human placental tissue throughout gestation provides the first insights into trophoblast dysfunction in pregnancy pathologies. The depletion of side-population trophoblasts in growth restricted placentae may contribute to poor placental function.

Keywords: Fetal growth restriction; Human trophoblast stem cell; Placenta; Pregnancy.