Understanding monocyte recruitment patterns to the maternal-fetal interface in preeclampsia

Introduction:: Maternal monocytes adapt during pregnancy to maintain immune protection while providing immunotolerance to fetal cells. Much of this behavioral adaptation occurs from the influence of the syncytiotrophoblast cells on the monocytes as they circulate through the maternal fetal interface (Mincheva‐Nilsson & Baranov, 2014). Preeclampsia (PE) affects 2-8% of pregnancies and is a leading cause of maternal morbidity and mortality. Limited diagnostic measures exist, and delivery is the only “cure”(Ives et al., 2020). Researchers believe preeclampsia stems from placental malperfusion caused by syncytiotrophoblast stress (Redman et al., 2021). It remains unanswered whether this stress derives from prolonged placental hypoxia or via a hypoxia-reperfusion type injury (Hung et al., 2002; Soleymanlou et al., 2005). Syncytiotrophoblast stress alters cellular signaling to circulating monocytes (Göhner et al., 2017), and the latter become more pro-inflammatory in PE (Alahakoon et al., 2018; Al-ofi et al., 2012). Literature is unclear how these signaling changes in preeclampsia affect monocyte trafficking to the maternal-fetal interface. As circulating monocytes are easily accessible, understanding their behavioral changes in PE provides insight into novel diagnostic methods or therapeutic targets.

The aim of this study was threefold: to determine how monocyte recruitment changes in PE, which factor predominantly influences migration, and which placental stress model most accurately models these results in vitro.


Materials and Methods:: Monocyte recruitment was assessed via a Boyden Chamber Assay. Naïve or TGF-β1 conditioned THP-1 monocytes (ATCC) were placed in the upper well of the chamber. Placental-explant media from PE and non-PE patients (Magee-Womens Research Institute, Pittsburgh, PA) was placed in the bottom well of the chamber. For in vitro studies, conditioned media from BeWo B-30 cells (a placental choriocarcinoma line) cultured under hypoxia or hypoxia-reperfusion was placed in the bottom well.


Results, Conclusions, and Discussions:: Results

Monocyte recruitment depended upon the gestational age of the placenta. For samples < 35 weeks gestation, migration significantly decreased in the PE samples vs. the non-PE samples. For samples >35 weeks gestation, naïve monocytes migrated equally to non-PE and PE explant media. Similar to the naïve monocytes, THP-1 monocytes preconditioned with TGF-β1 migrated equally to both non-PE and PE explant media at 35 weeks gestational age. However, preconditioned monocytes exhibited significantly higher rates of migration overall compared to the naïve monocytes. Finally, no statistical differences were observed in monocyte migration to conditioned media between control, hypoxic, and hypoxic-reperfused placental cells.

Discussion & Conclusions

In vitro models of hypoxia and hypoxia-reperfusion injury induced levels of migration similar to the healthy control, mimicking monocyte trafficking in late-onset PE. However, it remains unclear how to effectively model the monocyte recruitment patterns observed in early-onset PE.

Our findings indicate placental factors secreted in early-onset PE decrease monocyte migration to the maternal-fetal interface. It remains unanswered whether this change is a protective mechanism or a potential therapeutic target. The difference in migration results between early-onset and late-onset PE groups further confirms these disease subsets possess different etiologies. Monocyte inflammation more strongly influenced migration than placental disease state, implying the onset of PE can be predicted by assaying monocyte behavior.


Acknowledgements (Optional): : This work was funded by the Dowd Fellowship from the College of Engineering at Carnegie Mellon University. The authors would like to thank Philip and Marsha Dowd for their financial support and encouragement.

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