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Preterm birth skews the developmental trajectory of myeloid-derived suppressor cells in the first 48 hours of life: single-cell transcriptomics and inferred intercellular communication

ABSTRACT: Background: Prematurity is a leading cause of neonatal and childhood mortality, with infections driving early deaths. Innate immunity provides frontline defense after birth and is shaped in part by myeloid-derived suppressor cells (MDSCs). The role of MDSCs in regulation of neonatal immunity, especially in the context of prematurity, remains elusive. We sought to understand the transcriptional landscape of neonatal immune myeloid regulators, specifically differences between preterm and full-term neonates. Insight into specific cellular networks could help understand how to skew preterm MDSCs’ development towards classical immunotolerant and anti-microbial mechanisms. Methods: This cross-sectional study used single-cell RNA sequencing to characterize the neonatal MDSC transcriptional landscape, developmental trajectories, and predicted signaling networks within 48 hours after birth. Peripheral blood mononuclear cells were isolated from 7 preterm neonates (<36 weeks gestational age), 6 full-term neonates (>37 weeks), and 6 healthy adult (21-45 years old, control). Primary exposure was premature birth and neonatal intensive care hospitalization from a single-center, academic tertiary care hospital between 2023 – 2024. Results: Among ~339,000 cells, preterm neonates exhibited enrichment of polymorphonuclear MDSCs (10.6%±5.3%) vs full-term (2.6%±1.3%) and adults (0.4%±1.3%). Trajectory analysis identified a prematurity-associated differentiation branch characterized by inflammatory signaling, mitochondrial stress, and heightened protein-translation programs, distinct from a conserved, tolerogenic MDSC trajectory present across ages. Cell-communication modeling showed intensified outgoing and incoming signaling via ADGRE, RESISTIN, TGF-β, ANNEXIN, and ICAM networks. Antigen presentation signatures suggested preserved MHC-I output and diminished MHC-II interactions in neonates, with increased MHC-I input to preterm polymorphonuclear MDSCs. Conclusions: Prematurity is associated with early divergence of MDSC maturation toward an inflammatory and metabolically stressed PMN-MDSC state with altered immune communication. These findings identify cellular mechanisms that may contribute to the heightened tissue damage and infection susceptibility of preterm neonates and highlight MDSC signaling as a potential target for early-life immunomodulatory interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326288 | GEO | 2026/05/18

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

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Preterm birth skews the developmental trajectory of myeloid-derived suppressor cells in the first 48 hours of life: single-cell transcriptomics and inferred intercellular communication

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