Volume 450, Issue 2, 15 July 2025, 114684Author links open overlay panel, , , , , Highlights•

Third-trimester SpTSCs have trophoblast stem cell differentiation capacity.

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SpTSC from growth restricted (FGR) placentae proliferate more slowly.

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FGR SpTSC are more susceptible to intrinsic apoptosis.

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FGR SpTSC have altered differentiation capacity.

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Differences in SpTSC apoptosis may result from the paracrine environment.

Abstract

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.

Keywords

Placenta

Side-population trophoblasts

Trophoblast stem cells

Fetal growth restriction

Data availabilityTranscriptomic data has been deposited in NCBI GEO and accession numbers for data are available in Supplementary Table 1. All other imaging data is available from authors on request.

© 2025 The Authors. Published by Elsevier Inc.