Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration

Birth asphyxia is a frequent cause of perinatal morbidity and mortality and treatment options are very limited. Our aim was to determine the effects of treatment with bone marrow-derived mesenchymal stem cells (MSC) after neonatal hypoxic-ischemic brain injury (HI). Nine-day old mice were exposed to cerebral HI and endogenous cell proliferation was determined by BrdU-incorporation. Maximal endogenous cell proliferation, indicative for a trophic milieu, was observed at 3 days after HI. MSC transplantation at this time point decreased neuronal and oligodendrocyte loss when determined 21 days after HI by 42% and 31%, respectively. MSC treatment enhanced BrdU-incorporation in the ischemic hemisphere mainly in cells of recipient origin. The percentage of recently divided neurons and oligodendrocytes in hippocampus and cortex was increased after MSC transplantation. MSC treatment reduced the percentage of cortical and increased the percentage of hippocampal BrdU+-astrocytes. The percentage of BrdU+-microglia decreased after MSC treatment. Motoric behavior in the cylinder rearing test at 10 and 21 days after HI was significantly improved by MSC treatment 3 days after the insult. Moreover, even when treatment was started at 10 days after HI, there was a significant reduction in lesion size and improvement of behavioral outcome. Our data show that MSC treatment after neonatal HI brain damage improved functional outcome, reduced lesion volume, increased differentiation of recently divided cells towards neurons and oligodendrocytes and decreased proliferating inflammatory cells. We propose that MSC transplantation is a powerful treatment to improve behavioral outcome and cerebral lesion volume after neonatal brain damage via stimulation of endogenous repair processes.