Niemann Pick disease type C1 (NPC) is an autosomal recessive disease 
characterized by progressive neurological deterioration leading to premature 
death. In this study, we hypothesized that human umbilical cord blood-derived 
mesenchymal stem cells (hUCB-MSCs) have the multifunctional abilities to 
ameliorate NPC symptoms in the brain. To test this hypothesis, hUCB-MSCs were 
transplanted into the hippocampus of NPC mice in the early asymptomatic stage. 
This transplantation resulted in the recovery of motor function in the Rota Rod 
test and impaired cholesterol homeostasis leading to increased levels of 
cholesterol efflux-related genes such as LXRα, ABCA1, and ABCG5 while decreased 
levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase were observed in NPC 
mice. In the cerebrum, hUCB-MSCs enhanced neuronal cell survival and 
proliferation, where they directly differentiated into electrically active 
MAP2-positive neurons as demonstrated by whole-cell patch clamping. In addition, 
we observed that hUCB-MSCs reduced Purkinje neuronal loss by suppression of 
inflammatory and apoptotic signaling in the cerebellum as shown by 
immunohistochemistry. We further investigated how hUCB-MSCs enhance cellular 
survival and inhibit apoptosis in NPC mice. Neuronal cell survival was 
associated with increased PI3K/AKT and JAK2/STAT3 signaling; moreover, hUCB-MSCs 
modulated the levels of GABA/glutamate transporters such as GAT1, EAAT2, EAAT3, 
and GAD6 in NPC mice as assessed by Western blot analysis. Taken together, our 
findings suggest that hUCB-MSCs might play multifunctional roles in neuronal 
cell survival and ameliorating motor deficits of NPC mice.