TNF-α induces human neural progenitor cell survival after oxygen–glucose deprivation by activating the NF-κB pathway

• Published in: Experimental & molecular medicine Vol. 50; no. 4; pp. 1 - 14
• Main Authors: Kim, Miri, Jung, Kwangsoo, Kim, Il-Sun, Lee, Il-Shin, Ko, Younhee, Shin, Jeong Eun, Park, Kook In
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/1; 13/100; 13/2; 14/63; 38/39; 42/89; 45/44; 631/378/87; 631/532/2182; Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein - genetics; Baculoviral IAP Repeat-Containing 3 Protein - metabolism; Biomedical and Life Sciences; Biomedicine; Brain injury; Cell survival; Cell Survival - drug effects; Cells, Cultured; Cytotoxicity; Fetuses; Glucose - metabolism; Humans; Inflammation; Intracellular signalling; Ischemia; Medical Biochemistry; Molecular Medicine; mRNA; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; NF-kappa B - metabolism; NF-κB protein; Oxygen; Oxygen - metabolism; p38 Mitogen-Activated Protein Kinases; Progenitor cells; Signal transduction; Signal Transduction - drug effects; Stem Cells; Transplantation; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-018-0033-1

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. Stroke: creating a safe haven for neurological repair A potent “survival signal” for brain stem cells could enable effective regenerative therapies for stroke patients. Neural progenitor cells (NPCs) can develop into functional neurons and supportive glial cells, and researchers are tantalized by the prospect of using NPCs to repair damaged brain tissue. NPCs generally fail to flourish after transplantation, but a team led by Kook In Park at Yonsei University College of Medicine, South Korea, have found a signaling factor that helps these cells to survive and divide. Tumor necrosis factor-α (TNF-α) is associated with inflammation, but also protects neurons after a stroke. The researchers showed that pretreatment with TNF-α preserved NPCs exposed to starvation and oxygen-deprivation conditions in cell culture by activating critical cell survival pathways. These findings suggest that TNF-α may enable NPCs to survive long enough to repair post-stroke neurological damage.