Author ORCID Identifier

https://orcid.org/0000-0002-6408-1490

Date Available

7-20-2025

Year of Publication

2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Faculty

Ilhem Messaoudi

Faculty

David Feola

Abstract

Maternal environmental exposures and inflammation are known to impact fetal development in utero as well as increase the risk for chronic diseases later in life. Therefore, it is essential that we understand how the maternal environment alters placental structure and immune function.

Therefore, we isolated fetal (chorionic villous) tissues from the placentas of healthy pregnant participants (control) and those with inflammatory conditions, including SARS-COV-2 infection, pregravid obesity, and opioid use disorder. Isolated placental leukocytes were subjected to a series of assays to uncover the phenotypic, functional, and transcriptional (single-cell RNA-sequencing) landscape of placental immune cells. Additional placental tissues were subjected to H&E staining, reviewed for pathologies, and further interrogated by Visium spatial transcriptomics. We leveraged an in vitro model of umbilical cord blood-derived microglia-like cells (iMGL) to investigate microglia morphology, phenotype, function, and transcriptional profiles.

Our results indicated that maternal inflammation impairs placental perfusion/development and was accompanied by an increased inflammatory milieu in the decidua and chorionic villous. Furthermore, markers of angiogenesis and placental development differed in samples from inflamed compared to non-inflamed women across both placental compartments in line with our findings of increased features of vascular malperfusion. Spatial transcriptomics revealed aberrant frequencies of activated/inflammatory epithelial, stromal, trophoblast, and immune cells and modified processes associated with inflammation and angiogenesis across placental tissues. Our flow cytometry and single-cell RNA sequencing data highlighted the varied abundance of placental immune cells, including increased infiltration of maternal macrophages in fetal chorionic villous. Finally, we also studied fetal neurodevelopment using iMGL derived from inflammation-exposed pregnancies. They exhibited an ameboid-like (activated) phenotype, accompanied by dysregulated expression of microglia activation markers, impaired phagocytic capacity, but increased secretion of inflammatory mediators.

Altogether, these findings suggest a profound impact of maternal inflammation on the maternal-fetal interface, and that maternal environment can have a profound impact on newborn outcomes.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2025.284

Funding Information

These studies were supported by:

  • National Institute on Drug Abuse (POPI: Placenta, Opioids and Perinatal Implications - 1R01DA059152-01 IM),
  • National Institute of Health (Helping to End Addiction Long-term initiative supplement - 7R01AI145910-05S1 IM),
  • UK Center for Clinical and Translational Science (Substance Use Disorder Pilot Grant - 5UL1TR001998-07 IM, PG and TL1 training program - TL1TR001997 HT),
  • UK Substance Use Research Priority Area pilot funds supported by the Vice President for Research (HT).
  • Kentucky Opioid Response Effort (KORE) via Substance Abuse and Mental Health Services Administration (SAMHSA) Grants, H79TI081704, H79TI083283,
  • data management system that is hosted by UK with grant support from NIH CTSA UL1TR001998.

Additional Files
Chapter 2_Supplemental Table 1.xlsx (235 kB)
Chapter 2 Supplemental Table 1
Chapter 2_Supplemental Table 2.xlsx (114 kB)
Chapter 2 Supplemental Table 2
Chapter 3_Supplemental Table 1.xlsx (2791 kB)
Chapter 3 Supplemental Table 1
Chapter 3_Supplemental Table 2.xlsx (64 kB)
Chapter 3 Supplemental Table 2
Chapter 3_Supplemental Table 3.xlsx (1435 kB)
Chapter 3 Supplemental Table 3
Chapter 4_Supplemental Table 1.xlsx (11 kB)
Chapter 4 Supplemental Table 1
Chapter 4_Supplemental_Table 2.xlsx (7441 kB)
Chapter 4 Supplemental Table 2
Chapter 4_Supplemental_Table_3.xlsx (471 kB)
Chapter 4 Supplemental Table 3
Chapter 5_Supplemental Table 1.xlsx (10 kB)
Chapter 5 Supplemental Table 1
Chapter 5_Supplemental Table 2.xlsx (5090 kB)
Chapter 5 Supplemental Table 2
Chapter 5_Supplemental Table 3.xlsx (434 kB)
Chapter 5 Supplemental Table 3
Chapter 6_Supplemental Table 1.xlsx (610 kB)
Chapter 6 Supplemental Table 1
Chapter 6_Supplemental Table 2.xlsx (35 kB)
Chapter 6 Supplemental Table 2
Chapter 6_Supplemental Table 3.xlsx (13 kB)
Chapter 6 Supplemental Table 3
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