Optimizing intranasal mesenchymal stem cell therapy for neonatal brain injury: advancing therapeutic approaches and strenghtening insights

Neonatal hypoxic-ischemic (HI) brain injury is a leading cause of long-term neurological impairment in newborns. While current treatments are limited, intranasal mesenchymal stem cell (MSC) therapy has shown safety in humans and the potential to repair HI brain injury in preclinical studies. Although its potential, MSC therapy remains only partially effective and its mechanisms not fully understood. Notably, MSCs can be conditioned to improve efficacy and target specific repair processes. This thesis aimed to enhance intranasal MSC potency for treating HI brain injury by exploring various optimization strategies. This thesis provides novel insights into the chemotactic cues essential for migration of MSCs to the HI brain and identifies new targets for the future optimization of MSC migration. We demonstrated that hypoxic preconditioning is a promising optimization strategy to enhance the neuroregenerative and migratory potential of MSCs and thereby increases the therapeutic efficacy of intranasal MSC therapy. Additionally, we showed that while oral supplementation with lysophosphatidylcholine-bound n-3 polyunsaturated fatty acids provided neuroprotective effects as a standalone therapy, it did not provide additional therapeutic benefits on top of MSC therapy under the treatment regime investigated in this thesis. Lastly, we developed a novel method for assessing early neurodevelopmental outcome in social communication in a mouse model for neonatal HI brain injury, allowing the investigation of causes of and treatments for social communication impairments following HI. Altogether, this thesis demonstrates that by deepening our understanding of the mechanisms underlying intranasal MSC therapy for the neonatal HI-injured brain and by enhancing treatment efficacy, we are moving closer to implementing optimized MSC therapy for diverse populations of infants with neonatal brain injury, thereby advancing their future prospects.