Altered placental immune cell composition and gene expression with isolated fetal spina bifida

ProblemFetal spina bifida (SB) is more common in pregnant people with folate deficiency or anomalies of folate metabolism. It is also known that fetuses with SB have a higher risk of low birthweight, a condition that is typically placental-mediated. We therefore hypothesized that fetal SB would associate with altered expression of key placental folate transporters and an increase in Hofbauer cells (HBCs), which are folate-dependent placental macrophages.Method of studyFolate receptor-alpha (FR alpha), proton coupled folate receptor (PCFT), and reduced folate carrier (RFC) protein localization and expression (immunohistochemistry) and HBC phenotypes (HBC abundance and folate receptor-beta [FR beta] expression; RNA in situ hybridization) were assessed in placentae from fetuses with SB (cases; n = 12) and in term (n = 10) and gestational age (GA) - and maternal body mass index - matched (n = 12) controls without congenital anomalies.ResultsCases had a higher proportion of placental villous cells that were HBCs (6.9% vs. 2.4%, p = .0001) and higher average HBC FR beta expression (3.2 mRNA molecules per HBC vs. 2.3, p = .03) than GA-matched controls. HBCs in cases were largely polarized to a regulatory phenotype (median 92.1% of HBCs). In sex-stratified analyses, only male cases had higher HBC levels and HBC FR beta expression than GA-matched controls. There were no differences between groups in the total percent of syncytium and stromal cells that were positive for FR alpha, PCFT, or RFC protein immunolabeling.ConclusionsHBC abundance and FR beta expression by HBCs are increased in placentae of fetuses with SB, suggesting immune-mediated dysregulation in placental phenotype, and could contribute to SB-associated comorbidities.