Research Article: Integrated single-cell multi-omics analysis delineates neonatal immune dysregulation associated with gestational diabetes mellitus
Abstract:
Gestational diabetes mellitus (GDM) is a common pregnancy complication which could induce immune dysfunction. Although intrauterine hyperglycemia impairs fetal immune development, its cell-type specific effects on neonatal immune cells, and cell?cell communication remain unclear.
In this pilot study, we performed integrated 5? single?cell RNA sequencing and TCR repertoire analysis of cord blood mononuclear cells from two GDM and one type 2 diabetes mellitus (T2DM) mother–neonate pairs, with public healthy cord blood data (GSE157007) as controls. After quality control, 50,656 cells were analyzed using Seurat, scRepertoire, SCENIC, Monocle 2, decoupleR, and CellChat.
Myeloid lineage expansion and reduced naive T?cell proportions have been found in hyperglycemia?exposed cord blood. TCR analysis revealed mild clonal diversity compression, a shift toward shorter CDR3 lengths, and fewer ultralong CDR3 sequences in hyperglycemia?exposed cord blood. The Tpex?like cell population, which co?expresses stemness markers (TCF7, BACH2), early development markers of T cells (IKZF1, IKZF2) and the pre?exhaustion transcription factor TOX, was enriched in cord blood from GDM and T2DM neonates. This subset displayed elevated activity of TGF-?, MAPK and PI3K signaling pathways and predominantly resided within unexpanded T cell clonotypes. Pseudotime trajectory profiling indicates that Tpex-like cells reside at an intermediate differentiation state between precursor and effector T?cell populations. Cell communication analysis indicated increased immune interaction strength in GDM cord blood, with enrichment of pro?inflammatory pathways (SEMA4, IL?16, SIRP), whereas homeostatic pathways (LAIR1, GALECTIN) dominated in healthy controls.
We characterized multi-layered neonatal immune dysregulation observed in the setting of GDM?associated intrauterine hyperglycemia. Tpex?like cells represent a candidate cellular state linked to early immune changes in GDM offspring. We firstly identified candidate molecular signatures for subsequent mechanistic and translational exploration. These pilot findings require validation in larger independent cohorts.
Introduction:
Gestational diabetes mellitus (GDM) is a common pregnancy complication which could induce immune dysfunction. Although intrauterine hyperglycemia impairs fetal immune development, its cell-type specific effects on neonatal immune cells, and cell?cell communication remain unclear.
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