Single-cell profiling of the liver in offspring with intrauterine hyperglycemia reveals acute-phase response deficiency

Gestational diabetes mellitus (GDM) has long-term effects on offspring health. In the development of this chronic disease, inflammatory profiles play important roles. However, the assessment of GDM fetuses for their inflammatory status has been limited. Thus, single-cell RNA sequencing (scRNA-seq) is urgently needed to delineate the inflammatory characteristics of offspring with intrauterine hyperglycemia (IHG). A mouse IHG model was induced by streptozotocin (STZ). Liver samples of offspring at the fetal and adult periods were collected for scRNA-seq analysis and further experiments. CytoTRACE and Monocle were used for the developmental analysis of fetal liver after dimension reduction and clustering. The CellChat algorithm was applied for the cellular interaction analysis of adult livers. A lipopolysaccharide (LPS)-induced sepsis model was established in adult offspring to evaluate the immune response. Subsequently, primary cell flow cytometry (FCM) of the bone marrow (BM) and liver was performed for myeloid lineage detection. Finally, the transcriptional and translational levels of acute-phase response cytokines were quantified. Our study has mapped the single-cell profile of the livers in offspring with IHG. Myeloid polarization was identified, accompanied by the developmental retardation of multiple cell lineages in IHG offspring. In adults, myeloid polarization was restored to some extent, while the proinflammatory potential of these myeloid cells seemed to be deeply molded. Adult offspring with IHG also showed a deficiency in the acute-phase response in the LPS-induced sepsis model. The single-cell profile of the livers from offspring with IHG highlighted the comprehensive inflammatory status of the myeloid lineage and hinted at acute-phase response deficiency in sepsis.