Therefore, several clinical trials are currently investigating the efficacy and safety of MSCs as a treatment option for various pathologies. We have previously shown in a mouse model of neonatal HI brain damage that intranasal administration of murine MSCs significantly improves motor and cognitive behavior and reduces cerebral lesion volume. In contrast to current pharmacological therapies for neonatal HI, we found that MSC treatment has a long therapeutic window of 10 days after the insult. Studies from our group and others have shown that intracranial and intravenous injection of murine MSCs actively promote proliferation and differentiation of neuronal and glial precursor cells as well as axonal regeneration. Moreover, MSCs have been shown to exert strong anti-inflammatory properties and to modulate immune responses, for example by suppressing the proliferation of T cells and B cells in various disease models such as graft-versus-host disease. Before MSCs can be used in the clinic for the treatment of neonatal brain damage, the neuroregenerative potential of human MSCs has to be determined. A few studies in the adult rodent MCAO model for Wortmannin stroke have investigated the efficacy of hMSCs to repair stroke induced brain lesion and behavioral deficits, but none have studied the effects of hMSCs on neonatal encephalopathy. The results from these studies show that hMSCs improve motor behavior, decrease lesion size and enhance angiogenesis. In our study, we used an in vitro assay to assess the capacity of hMSCs to induce mouse neural stem cell to differentiate towards neuronal and glial cell fates. Moreover, we determined in vivo whether hMSCs are able to migrate towards the injury site in our mouse model of neonatal HI brain injury and which chemotactic factors may mediate MSC migration to the lesion. Most importantly, we investigated whether treatment with hMSCs improves motor behavior and decreases lesion size and gliosis following HI injury in the neonatal mice. Our study shows that human MSCs have the capacity to promote neuroregeneration. This finding is reflected by our results showing that intranasal administration of hMSCs significantly improves motor behavior, and decreases lesion size and scar formation at 28 days after HI brain damage in neonatal mice. Furthermore, our in vitro results demonstrate that human MSCs are capable of inducing mNCSs to differentiate towards astrocytic and neuronal cell fate. This suggests that hMSCs do not need cell to cell contact with neural stem cells, but rather promote endogenous neurogenesis and lesion repair by the secretion of neurotrophic factors. We also show that hMSCs reach the damaged brain region in the mouse within 24 hours after intranasal administration. Importantly, our work also provides new insight into the chemotactic factors that may regulate MSC migration towards the lesion site. Our results show that the chemokine CXCL10 is strongly upregulated at 10 days following HI.