New Insights into Cellular Senescence and Oxygen Effects on Trophoblast Differentiation

Document Type

Article

Publication Date

8-9-2024

Keywords

JGM

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Trophoblast cell functions are important for healthy decidualization and placentation throughout mammalian embryonic development. Trophoblast stem cells (TS) in the placental villi differentiate into extravillous trophoblasts (EVT), which invade uterine spiral arteries along the endometrium, establishing maternal blood flow into the placenta, enabling nutrient, gas and waste exchange between the mother and the fetus. EVT migration and invasion, crucial for healthy placentation and defects, result in placental disorders. Similarly, placental senescence features are known to be critical in placental aging and have been linked to trophoblasts. However, knowledge about specific developmental senescence in trophoblast is very limited. Oxygen gradients are important in EVT differentiation and are established by spiral artery remodeling. Similarly, classic features of senescence have also been described in TS and EVT cells. Defects in establishing the oxygen gradient and aberrant senescence expression have both been independently linked with placental disorders (e.g. preeclampsia and fetal growth restriction).

This study investigates the effects of senolytic drug on differentiating EVT to explore important senescence features important in development. We utilized transcriptomic, antibody-based biomolecular, and functional assays to investigate how Dasatinib+ Quercetin (D+Q) senolytic drug and oxygen level affected the morphology and biomarkers critical in EVT differentiation. Our data reveals that EVT has optimal differentiation in 3% oxygen conditions compared to higher oxygen; suggesting that oxygen inherently modulates senescence differentiation features. Immunofluorescence data revealed that EVT expressing Ki67 and LAMINB1 are less vulnerable to the effect of removed senescence. EVT expressing p21+, p57+ are targeted by senolytic drug. Additionally, we found that EVT precursors are prone to D+Q treatment, unlike mature EVT which continue proliferating despite the exposure to drug.

These findings provide a valuable understanding of important senescent markers in trophoblast cells critical for the continuation of a healthy pregnancy which is valuable to understand placental disorders. Moreover, these same features of developmental senescence are valuable to understand the senescence features associated with aging in disease later in human life.

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