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Therapeutic Effects of Human Mesenchymal Stem Cells on Traumatic Brain Injury in Rats: Secretion of Neurotrophic Factors and Inhibition of Apoptosis

Other Title
뇌외상 동물모델에서 인간 골수유래 중간엽줄기세포의 치료효과에 관한 연구: 신경성장인자의 분비와 세포사멸 억제
김, 화정
Doctor (2009)
Traumatic brain injury (TBI) leads to secondary brain insults, which often result in permanent functional loss of damaged cells. Many researchers have looked for methods that will reduce secondary brain damage since there is no effective therapeutics to recover functional loss of damaged tissues. The severity of the secondary mechanism of TBI depends upon two factors: injury severity (mild, moderate or severe) and location of the primary injury. Secondary brain damage has been known to involve neuroinflammatory, apoptotic and oxidative stress mechanisms which are mainly dependent on intracerebral production of cytokines. The development of an experimental model that resembles pathological and functional changes in human brain is critical in providing an effective therapeutics for human TBI. The controlled cortical impact (CCI) model is frequently used for TBI models in animals because it enables the physical adjustment of injury levels and has close pathological resemblance to actual human TBI. However, little is known about the severity of brain injury according to injury-induction parameters. In this study, morphological changes and behavioral scores after TBI in rats were measured according to the different impact velocity and depth of deformation; these parameters were further investigated to provide a guideline for establishing a TBI animal model. In recent years, there has been increasing interest in the use of mesenchymal stem cells (MSCs) as cell therapy for TBI. To investigate the therapeutic effects and their possible mechanisms of human bone marrow-derived mesenchymal stem cells (hMSCs) in the rat model of TBI, we analyzed the neurological functions and in vivo growth factor production. Male Sprague-Dawley rats were injured with a CCI device and divided into two experimental groups: those which received hMSCs intravenously 24 hours after TBI and those injected with saline only as placebo. For the analysis of in vivo production of growth factors, the animals were sacrificed 2, 8, 15, and 29 days (n=6 for each group at each day) after TBI, and the injured hemispheres were extracted. We measured the level of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the brain, using enzyme-linked immunosorbent assay (ELISA). The neurological function assessed by rotarod motor test and modified neurological severity scores (mNSS) recovered significantly in the animals treated with hMSCs 15 days after TBI. Quantitative ELISA studies showed that the in vivo expressions of NT-3 and NGF 2 and 8 days after TBI and the in vivo expression of BDNF 2 days after TBI were significantly increased (p < 0.05) in the treated group compared to the placebo group. Additionally, NGF and BDNF mRNA expression were up-regulated 2 and 8 days after TBI in the animals treated with hMSCs. Immunohistochemical studies showed that the expression of NGF, BDNF, and NT-3 were stronger in the injured hemispheres of the treated group compared to those of the placebo group 2 days after TBI. Western blotting showed that pAkt expression was up-regulated 2 days after TBI and caspase-3 cleavage was significantly decreased 8 days after TBI in hMSCs group. Our results suggest that treatment of TBI with hMSCs during the acute phase can enhance the functional outcome and the augmentation of neurotrophic factors in the injured hemisphere can be one of possible mechanisms for functional recovery by reducing neuronal apoptosis.
traumatic brain injuryhuman mesenchymal stem cellsneurotrophic factorsapoptosisfunctional recovery
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김, 화정
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