148. Treatment of Neonatal Brain Injury with Mesenchymal Stem Cells

Abstract

Birth asphyxia leading to brain damage is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. We determined whether treatment with mesenchymal stem cells (MSC) improves outcome in a mouse model of neonatal hypoxic–ischemic unilateral brain injury and investigated underlying mechanisms. Intracranial injection with MSC at 3 days (MSC-3) or 3 + 10 days (MSC-3+10) after neonatal hypoxia–ischemia (HI) in p9 mice, improved sensorimotor function and reduced lesion size. Ipsilesional corticospinal tract-tracing with biotinylated dextran-amine (BDA) showed that HI caused axonal rewiring towards the contralateral hemisphere and reduced BDA-labelling of the contralateral spinal cord. MSC-3+10-treatment partially restored contralateral spinal cord BDA-staining, indicating enhanced axonal remodelling. These positive effects on structure and function are not due to engraftment of MSC in the brain as survival of transplanted MSC is very limited. However, MSC-treatment induces marked changes in the gene expression of growth-factors and cytokines. Therefore, we propose that MSC treatment induced regeneration by regulation of the endogenous growth factor milieu rather than by replacing damaged tissue. In search for a more clinically applicable route of MSC administration, we investigated the potential use of the nasal route. Interestingly, intranasal MSC treatment at 10 days after HI improved sensorimotor function and lesion volume to the same extent as intracranial MSC administration. In conclusion the nasal route can be used for MSC transplantation.