Intranasal stem cell treatment ameliorates neuroinflammation and myelin aberrations in fetal growth-restricted rat pups.

Fetal growth restriction (FGR), a condition in which a fetus fails to reach its full growth potential, affects approximately 30 million infants worldwide each year and increases the risk of long-term neurodevelopmental deficits. Currently, no effective therapies exist to mitigate FGR-induced neurological impairments. Mesenchymal stem cells (MSCs) have emerged as a promising neuroregenerative therapeutic approach. Here, we used the reduced uterine perfusion pressure (RUPP) rat model of chronic placental hypoperfusion-induced FGR. We explored, for the first time, intranasal MSC administration in the early postnatal period in growth-restricted offspring as a minimally invasive and clinically feasible cell delivery approach. RUPP pups received human Wharton's jelly-derived MSCs or vehicle intranasally at postnatal day 5 (P5) or P10, and neuropathological outcomes were assessed at P20. Pups from sham-operated dams served as controls. Intranasal MSC treatment, particularly at the early postnatal treatment timepoint (P5), ameliorated key neuropathological outcomes, as evidenced by improved brain weight and cortical myelination, enhanced oligodendrocyte maturation, and dampened microglial activation compared to vehicle-treated RUPP pups. Functional impairments, measured between P13 and P56 by eye opening, grip strength, and foot faults on the tapered beam walk, showed no significant improvement. Our findings provide proof-of-concept that early-life stem cell therapy provides histological improvements in RUPP-induced brain abnormalities. Although further optimization is needed to establish whether these effects translate into functional benefits, intranasal MSCs represent a promising, minimally invasive neuroregenerative strategy with potential clinical relevance for newborns affected by chronic placental insufficiency-induced FGR.