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J Neurotrauma. 2019 Aug 20. doi: 10.1089/neu.2019.6422. [Epub ahead of print]

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

Shahror RA1,2, Linares GR3,4, Wang Y5, Hsueh SC1,2, Wu CC2,6,7, Chuang DM1,3, Chiang YH1,2,6,7, Chen KY1,2.

Author information

1
1Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.
2
2TMU Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan.
3
3Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
4
4Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
5
5Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
6
6Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan.
7
7Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

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 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.

KEYWORDS:

fibroblast growth factor 21; mesenchymal stem cells; neurogenesis; spatial learning and memory; traumatic brain injury

PMID:
31298621
DOI:
10.1089/neu.2019.6422

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