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

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.