Transplantation of Mesenchymal Stem Cells Overexpressing Fibroblast Growth Factor 21 Facilitates Cognitive Recovery and Enhances Neurogenesis in a Mouse Model of Traumatic Brain Injury

Abstract

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 TBIinduced 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.

The Effect of Oral Mucosal Mesenchymal Stem Cells on Long-Term Brain Edema and Lesion, Anxiety-Like Behavior, and Cognitive and Motor Outcomes in Experimental Traumatic Brain Injury

“…In a study conducted by Zhou et al (2019), it was shown that MSCs administration ameliorated neurological dysfunction and also memory and learning impairment after TBI [53]. Transplantation of MSCs overexpressing broblast growth factor 21 (FGF-21) as a neuroprotective protein recovered hippocampal-dependent and independent learning and memory de cits in a mouse model of TBI [54]. In a study, it was shown that BMSCs transplantation could improve cognitive impairment through upregulation of hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion [55].…”

Valproic Acid Promotes Early Neural Differentiation in Adult Mesenchymal Stem Cells Through Protein Signalling Pathways

“…In the ClueGo analysis, the FGFR signalling pathway is proximal to several downstream processes, particularly in cerebral cortex development and neuron maturation. In a recent study by Shahror et al [52] it was shown that MSCs over expressing FGF21 transplanted to a mouse model enhanced neurogenesis and recovery. Furthermore, their results also show the FGF21 promoted maturation of the hippocampal neurons.…”

Tracking Superparamagnetic Iron Oxide-labeled Mesenchymal Stem Cells using MRI after Intranasal Delivery in a Traumatic Brain Injury Murine Model

“…Mesenchymal stem cells (MSC) are attractive candidates for stem cell-based therapies in treatments of central nervous system (CNS) disorders and injuries in humans. Moreover, MSCs have been used as a vehicle for the delivery of therapeutic proteins at injury sites 1,2 . In recent years, promising innovations have been developed to establish 1) novel routes of cell delivery and 2) cell tracking for stem cell-based therapies of CNS disorders.…”