Integrated single-cell multi-omics analysis delineates neonatal immune dysregulation associated with gestational diabetes mellitus
- 1Department of Hematology, First Affiliated Hospital of Jinan University , ,
- 2Gynaecology and Obstetrics Department, Guangzhou Panyu District Maternal and Child Health Hospital , , ,
- 3Department of Systems Biomedical Sciences, School of Medicine, Jinan University , ,
Abstract
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.
Methods: 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.
Results: 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-β, 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.
Discussion: 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.
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BibTeX
@article{he2026integrated,
title = {{Integrated single-cell multi-omics analysis delineates neonatal immune dysregulation associated with gestational diabetes mellitus}},
author = {Renke He and Zhipeng Liu and Qingju Meng and Kaiyue Wu and Junwei Wu and Yanqiu Li and Oscar Junhong Luo and Yangqiu Li},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1924940},
url = {https://europepmc.org/article/PMC/PMC13661941},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrated single-cell multi-omics analysis delineates neonatal immune dysregulation associated with gestational diabetes mellitus
AU - Renke He
AU - Zhipeng Liu
AU - Qingju Meng
AU - Kaiyue Wu
AU - Junwei Wu
AU - Yanqiu Li
AU - Oscar Junhong Luo
AU - Yangqiu Li
PY - 2026
DA - 2026/09/30
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1924940
UR - https://europepmc.org/article/PMC/PMC13661941
AB - 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. Methods: 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. Results: 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-β, 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. Discussion: 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.
SN - 1664-3224
ER -