Traumatic brain injury (TBI) is a progressive and complex pathological condition that results in multiple adverse consequences, including impaired learning and memory. Transplantation of mesenchymal stem cells (MSCs) has produced limited benefits in experimental TBI models. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has neuroprotective effects, promotes remyelination, enhances angiogenesis, and elongates astrocytic processes. In this study, MSCs were genetically engineered to overexpress FGF21 in order to improve their efficacy in TBI. MSCs overexpressing FGF21 (MSC-FGF21) were transplanted to mouse brain by intracerebroventricular injection 24 h after TBI was induced by controlled cortical impact (CCI). Hippocampus-dependent spatial learning and memory, assessed by the Morris water maze test, was markedly decreased 3-4 weeks after TBI, a deficit that was robustly recovered by treatment with MSC-FGF21, but not MSC-mCherry control. Hippocampus-independent learning and memory, assessed by the novel object recognition test, was also impaired; these effects were blocked by treatment with both MSC-FGF21 and MSC-mCherry control. FGF21 protein levels in the ipsilateral hippocampus were drastically reduced 4 weeks post-TBI, a loss that was restored by treatment with MSC-FGF21, but not MSC-mCherry. MSC-FGF21 treatment also partially restored TBI-induced deficits in neurogenesis and maturation of immature hippocampal neurons, whereas MSC-mCherry was less effective. Finally, MSC-FGF21 treatment also normalized TBI-induced impairments in dendritic arborization of hippocampal neurons. Taken together, the results indicate that MSC-FGF21 treatment significantly improved TBI-induced spatial memory deficits, impaired hippocampal neurogenesis, and abnormal dendritic morphology. Future clinical investigations using MSC-FGF21 to improve post-TBI outcomes are warranted.
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