The Persistence of Trophoblast Stem Cells in Later Mouse Gestation: Insights into the Signalling Involved in Their Maintenance

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McGinnis, Avery Jane
Placenta , Trophoblast , Trophoblast Stem Cell , Stem Cell Antigen 1 , Eomes , Transforming Growth Factor Beta
Our group previously identified trophoblast populations expressing the characteristic mouse trophoblast stem (mTS) cell marker, Eomes, or the established stem and progenitor cell marker, Sca-1, that persist until E16.5 and proliferate in response to placental pathology. These findings support the maintenance of tissue-resident stem cells that help the placenta adapt to pathology throughout gestation. If such a population is identified, its characterization could the discovery of an analogous human TS cell population with clinical potential in the context of human placental pathology. During development, Eomes is restricted to the extraembryonic ectoderm and, by E7.5, to the chorion, after which its expression declines. The placental junctional zone and labyrinth layers are thought to develop exclusively from the ectoplacental cone and chorion, respectively. While it is well established that mTS cells express Eomes and that in vitro, they differentiate to all trophoblast subtypes, it is unknown if Eomes-positive (EomesPOS) trophoblast that reside in the chorion beyond E6.5 are restricted in their developmental potential. However, by utilizing a lineage tracing technique with complementary immunofluorescence staining, we found that EomesPOS trophoblast maintain the capacity to contribute to both placental layers in vivo and do so after E7.5. Approximately 85-90% of mTS cells express Sca-1, though its function is unknown. Transforming growth factor beta 1 (TGFB1), which plays a role in placental development and the proliferation/differentiation of trophoblast cells, is required for prolonged mTS cell maintenance in vitro. Previous investigations have demonstrated that Sca-1 can attenuate TGFB1 signalling, and TGFB1 signalling can attenuate Sca-1 expression. The Sca-1/TGFB1 relationship in mTS cells has not been explored. Our study revealed that Sca-1 expression did not affect TGFB1 signalling, nor did TGFB1 treatment downregulate Sca-1 expression. However, we identified that positive regulation of Sca-1 expression in mTS cells is mediated by activation of the TGFB superfamily receptor, ALK5, particularly by TGFB1. Collectively, these findings support a role for ALK5 signalling in sustaining Sca-1 within mTS cells. My MSc work provided further support that mTS cells may persist in the placenta into late gestation and provided insights into the microenvironmental conditions required for late gestation mTS cell maintenance.
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