Metabolic Reprogramming of Oligodendrocytes in Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) has been shown to adversely affect developing white matter, putting infants at risk for neurodevelopmental disability, including cerebral palsy. White matter injury (WMI) has been well documented in both human and animal studies of IUGR with sexual dimorphism. Currently, the underlying cellular mechanisms leading to WMI in IUGR remain poorly understood, but energy failure is a likely candidate.

To address these gaps, we evaluated for sex-specific changes to oligodendrocyte (OL) differentiation and the OL transcriptome, leveraging cell-specific epitope tagging and RNA isolation in a placental insufficiency-induced IUGR mouse model. OL mitochondrial respiration was further evaluated using primary cell isolation and Agilent Seahorse technology.

We found an early sex-specific arrest of OL differentiation in IUGR females, which was followed by late catch-up differentiation and proliferation. Cell-specific RNA sequencing demonstrated downregulation of genes involved in oxidative phosphorylation (OXPHOS) in IUGR. IUGR males demonstrated a greater downregulation of electron transport chain (ETC) genes and proteins than their IUGR female counterparts. Quantification of O4+ OL mitochondrial respiration also demonstrated decreased ATP generation in IUGR males via OXPHOS that was consistent with ETC gene and protein expression findings.

Our findings demonstrate sex-specific differences in OL differentiation and in mitochondrial metabolism in IUGR. These results provide insight into the different neurodevelopmental outcomes seen between IUGR males and females. These results also lay the foundation for investigation into targeted nutritional and pharmacologic management.