Abstract
Neural progenitor cells (NPCs) therapy offers great promise in hypoxic-ischemic (HI) brain injury. However, the poor survival of implanted NPCs in the HI host environment limits their therapeutic effects. Tumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that is induced in response to a variety of pathological processes including inflammation and immunity. On the other hand, TNF-α has protective effects on cell apoptosis and death and affects the differentiation, proliferation, and survival of neural stem/progenitor cells in the brain. The present study investigated whether TNF-α pretreatment on human NPCs (hNPCs) enhances the effectiveness of cell transplantation therapy under ischemic brain. Fetal brain tissue-derived hNPCs were pretreated with TNF-α before being used in vitro experiments or transplantation. TNF-α significantly increased expression of cIAP2, and the use of short hairpin RNA-mediated knockdown of cIAP2 demonstrated that cIAP2 protected hNPCs against HI-induced cytotoxicity. In addition, pretreatment of hNPCs with TNF-α mediated neuroprotection by altering microglia polarization via increased expression of CX3CL1 and by enhancing expression of neurotrophic factors. Furthermore, transplantation of TNF-α-treated hNPCs reduced infarct volume and improved neurological functions in comparison with non-pretreated hNPCs or vehicle. These findings show that TNF-α pretreatment, which protects hNPCs from HI-injured brain-induced apoptosis and increases neuroprotection, is a simple and safe approach to improve the survival of transplanted hNPCs and the therapeutic efficacy of hNPCs in HI brain injury.
Highlights
Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and severe neurological disability, including mental retardation, epilepsy, learning disabilities, and cerebralCells 2020, 9, 1195; doi:10.3390/cells9051195 www.mdpi.com/journal/cellsCells 2020, 9, 1195 palsy [1,2]
To monitor the survival of transplanted human NPCs (hNPCs) in HI-injured brain in vivo, we transduced hNPCs by infecting them with lentiviral particles encoding the firefly luciferase (Fluc) gene (Figure 1a)
Our results reveal that TNF-α pretreatment improved the viability of hNPCs in HI brain injury
Summary
Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and severe neurological disability, including mental retardation, epilepsy, learning disabilities, and cerebralCells 2020, 9, 1195; doi:10.3390/cells9051195 www.mdpi.com/journal/cellsCells 2020, 9, 1195 palsy [1,2]. The benefits of NPC therapy are limited by the poor survival, integration, differentiation, and functional neural connection in the inhospitable environment of the injured central nervous system (CNS) [6,7,8,9,10,11]. Strategies such as genetically modifying stem cells to overexpress pro-survival signaling-related or paracrine factors have been suggested to enhance the survival of transplanted cells and the effectiveness of cell transplant therapy [12,13,14,15]. Pretreatment of NPCs with pharmacological agents might result in significant cytoprotective effects and improve functional outcomes against CNS disorders [16,17,18]
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