제1저자 김미리(소아과학교실, BK21)
Exp Mol Med. 2018 Apr 6(4):14. doi: 10.1038/s12276-018-0033-1.
TNF-α induces human neural progenitor cell survival after oxygen-glucose deprivation by activating the NF-κB pathway.
Kim M1, Jung K2, Kim IS2, Lee IS2, Ko Y3, Shin JE4, Park KI5,6,7.
1Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea.2Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Korea.3Division of Biomedical Engineering, Hankuk University of Foreign Studies, Yongin, 17035, Korea.4Department of Pediatrics, Severance Children''s Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea.5Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea. firstname.lastname@example.orgYonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Korea. email@example.comDepartment of Pediatrics, Severance Children''s Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea. firstname.lastname@example.org.
Neural progenitor cell (NPC) transplantation has been shown to be beneficial in the ischemic brain. However, the low survival rate of transplanted NPCs in an ischemic microenvironment limits their therapeutic effects. Tumor necrosis factor-alpha (TNF-α) is one of the proinflammatory cytokines involved in the pathogenesis of various injuries. On the other hand, several studies have shown that TNF-α influences the proliferation, survival, and differentiation of NPCs. Our study investigated the effect of TNF-α pretreatment on human NPCs (hNPCs) under ischemia-related conditions in vitro. hNPCs harvested from fetal brain tissue were pretreated with TNF-α before being subjected to oxygen-glucose deprivation (OGD) to mimic ischemia in vitro. TNF-α pretreatment improved the viability and reduced the apoptosis of hNPCs after OGD. At the molecular level, TNF-α markedly increased the level of NF-κB signaling in hNPCs, and an NF-κB pathway inhibitor, BAY11-7082, completely reversed the protective effects of TNF-α on hNPCs. These results suggest that TNF-α improves hNPC survival by activating the NF-κB pathway. In addition, TNF-α significantly enhanced the expression of cellular inhibitor of apoptosis 2 (cIAP2). Use of a lentivirus-mediated short hairpin RNA targeting cIAP2 mRNA demonstrated that cIAP2 protected against OGD-induced cytotoxicity in hNPCs. Our study of intracellular NF-κB signaling revealed that inhibition of NF-κB activity abolished the TNF-α-mediated upregulation of cIAP2 in hNPCs and blocked TNF-α-induced cytoprotection against OGD. Therefore, this study suggests that TNF-α pretreatment, which protects hNPCs from OGD-induced apoptosis by activating the NF-κB pathway, provides a safe and simple approach to improve the viability of transplanted hNPCs in cerebral ischemia.