(537) Maternal COVID-19 and placental expression of senescence-associated secretory phenotype genes

Objective: Maternal COVID-19 increases the risk for adverse pregnancy outcomes related to placental dysfunction, including preeclampsia and stillbirth, however, the biologic basis remains underexplored. Based on recent work showing the association between placental senescence and preeclampsia, we hypothesized that senescence-associated secretory phenotype (SASP) genes are dysregulated in COVID-19 placentas.

Study Design: We analyzed a single-nucleus RNA sequencing dataset of placentas from symptomatic COVID-19 patients at birth (n=4) and gestational age-matched controls (n=4) to characterize the response of different trophoblast populations to COVID-induced stress. Differentially expressed gene (DEGs) in COVID-19 v. controls were identified for villous syncytiotrophoblasts (STB), membrane extravillous trophoblasts (EVT-M), and membrane cytotrophoblasts (CTB-M) using the Seurat (v4.3.0) in R given that these populations are likely sources of circulating placental proteins. Our analysis focused on DEGs belonging to a previously defined set of SASP genes.

Results: The baseline characteristics for COVID-19 patients and control groups were similar for maternal age (26 vs 28 years-old), gestational age (36 vs 38 weeks) and BMI (37 vs 34 kg/ m2). DEG analysis showed upregulation of distinct SASP pathway genes in STB, EVT-M, and CTB-M populations. Follistatin-like 3 (FSTL3) was significantly upregulated in COVID-19 samples across all cell populations, but predominantly expressed in EVT-M and CTB-M(P ≤ 0.0001)(Figure 1). In contrast, activin A (INHBA) was only upregulated in the STB and EVT-M populations, but predominantly expressed in STBs (P ≤ 0.0001)(Figure 2).

Conclusion: Compared with control placentas, trophoblast populations from COVID-19 positive patients showed an increased expression of senescence genes. Our data reveals cell type-specific expression of senescence genes, suggesting that SASP proteins in the maternal circulation have different sources. This increased expression of senescence genes among COVID-19 positive patients may provide potential insight into the link between COVID-19 and preeclampsia.