(1164) Comprehensive single-cell profiling of the maternal-fetal interface in Type 1 Diabetes

Individuals with type 1 diabetes (T1D), an autoimmune disorder with insulin deficiency and metabolic dysregulation, have increased risk of placental dysfunction and adverse pregnancy outcomes. The molecular mechanisms underlying pregnancy morbidity in T1D are poorly understood. We examined placental gene programs at the single-cell level in T1D pregnancies.

Study Design:

We collected 19 placental samples from T1D pregnancies (N=10) and healthy controls (N=9), balanced for fetal sex. We profiled maternal and fetal cells using 10x Genomics single-cell RNA sequencing. Genetic demultiplexing determined maternal/fetal cell origin. Differentially expressed genes (DEGs) between T1D and controls were identified across cell subclusters (threshold: fold change >1.5, FDR < 0.1). Pathway analysis (Ingenuity) was performed on subclusters with ≥50 DEGs.

Results:

Of 114 trophoblast, immune, and stromal subpopulations identified, 35 were dysregulated by T1D (Fig. 1). Villous cytotrophoblasts (VCTs), maternal CD14+ monocytes, fetal S100A8+ macrophages (Hofbauer subset), and fetal endothelial cells were most impacted. Dysregulated canonical pathways included upregulated oxidative phosphorylation and mitochondrial function in VCTs, altered activation patterns in macrophages, and dysregulated IL-4/13 and JAK-mediated cytokine signaling in fetal endothelial cells, indicating fetal inflammation (Fig. 2A). Multiple disease functions were upregulated in fetal endothelial cell subtypes: cell survival, leukocyte adhesion/migration, and angiogenesis (Fig. 2B). Glucose metabolism disorder pathways were upregulated in maternal and fetal macrophage subtypes.

Conclusion:

Examination of the maternal-fetal interface at the single-cell level revealed novel immune and metabolic gene pathways impacted by T1D. These findings suggest an impact of maternal T1D across the maternal-fetal interface that may have implications for offspring cardiometabolic programming.