Gang Ji1, Ming Liu1, Xiong-Fei Zhao2, Xiao-Yan Liu1, Qi-Lin Guo1, Zhu-Fei Guan3, Hou-Guang Zhou3, Jing-Chun Guo1. 1. State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. 2. Shanghai Angecon Biotechnology Co., Ltd., Shanghai, China. 3. Department of Geriatric Neurology, Huashan Hospital, Fudan University, Shanghai, China.
Abstract
AIM: Hypoxic-ischemic encephalopathy (HIE) is a common neurological disease in infants with persistent neurobehavioral impairments. Studies found that neural stem cell (NSC) therapy benefits HIE rats; however, the mechanisms underlying are still unclear. The current study investigated the efficacy and molecular events of human embryonic neural stem cells (hNSCs) in neonatal hypoxic-ischemic (HI) rats. METHODS: PKH-26-labeled hNSCs were intranasally delivered to P7 Sprague Dawley rats 24 h after HI. Neurobehavioral tests were performed at the indicated time after delivery: righting reflex and gait testing at D1, 3, 5, and 7; grid walking at D7 and 14; social choice test (SCT) at D28; and Morris water maze from D35 to 40. Protein expression was determined by Western blot analysis. Brain damage was assessed by cresyl violet staining and MBP staining. hNSC distribution and differentiation were observed by in vivo bioluminescence imaging and immunofluorescence staining. RESULTS: (1) hNSCs migrated extensively into brain areas within 24 h after the delivery, survived even at D42 with the majority in ipsi-hemisphere, and could be co-labeled with NeuN or GFAP. (2) hNSCs reduced the upregulation in cytosolic IL-1β, p-IκBα, and NF-κB p65 levels, whereas enhanced nuclear p65 expression in HI rats at D3 after the delivery. (3) hNSCs decreased HI-induced brain tissue loss and white matter injury at D42 after the delivery. (4) hNSCs improved neurological outcomes in HI rats in the tests of righting reflex (within 3 days), gait (D5), grid (D7), SCT (D28), and water maze (D42). CONCLUSION: Intranasal delivery of hNSCs could prevent HI-induced brain injury and improve neurobehavioral outcomes in neonatal HI rats, which is possibly related to the modulation of NF-κB signaling.
AIM: Hypoxic-ischemicencephalopathy (HIE) is a common neurological disease in infants with persistent neurobehavioral impairments. Studies found that neural stem cell (NSC) therapy benefits HIErats; however, the mechanisms underlying are still unclear. The current study investigated the efficacy and molecular events of human embryonic neural stem cells (hNSCs) in neonatal hypoxic-ischemic (HI) rats. METHODS: PKH-26-labeled hNSCs were intranasally delivered to P7 Sprague Dawley rats 24 h after HI. Neurobehavioral tests were performed at the indicated time after delivery: righting reflex and gait testing at D1, 3, 5, and 7; grid walking at D7 and 14; social choice test (SCT) at D28; and Morris water maze from D35 to 40. Protein expression was determined by Western blot analysis. Brain damage was assessed by cresyl violet staining and MBP staining. hNSC distribution and differentiation were observed by in vivo bioluminescence imaging and immunofluorescence staining. RESULTS: (1) hNSCs migrated extensively into brain areas within 24 h after the delivery, survived even at D42 with the majority in ipsi-hemisphere, and could be co-labeled with NeuN or GFAP. (2) hNSCs reduced the upregulation in cytosolic IL-1β, p-IκBα, and NF-κB p65 levels, whereas enhanced nuclear p65 expression in HIrats at D3 after the delivery. (3) hNSCs decreased HI-induced brain tissue loss and white matter injury at D42 after the delivery. (4) hNSCs improved neurological outcomes in HIrats in the tests of righting reflex (within 3 days), gait (D5), grid (D7), SCT (D28), and water maze (D42). CONCLUSION: Intranasal delivery of hNSCs could prevent HI-induced brain injury and improve neurobehavioral outcomes in neonatal HIrats, which is possibly related to the modulation of NF-κB signaling.
Authors: Michael C Veronesi; Mosa Alhamami; Shelby B Miedema; Yeonhee Yun; Miguel Ruiz-Cardozo; Michael W Vannier Journal: Am J Nucl Med Mol Imaging Date: 2020-02-25