Transplantation of Wnt4-modified Neural Stem Cells Mediate M2 Polarization to Promote Spinal Cord Injury Repair

Abstract Background: Neural stem cells (NSCs) transplantation has been considered as a potential strategy to reconnect the neural circuit after spinal cord injury (SCI) but the therapeutic effect was still unsatisfied because of the poor inflammatory microenvironment. Wnt4 has been considered to be neurogenesis and anti-inflammatory so that it would be an essential assistant agent for NSCs transplantation. To explore interaction between Wnt4-modified NSCs and macrophages; and the effect of Wnt4-modified NSCs on the inflammatory microenvironment of SCI is relevant for targeted and effective treatments that promote injured spinal cord repair. Methods: In vitro NSCs-macrophages co-cultured system was established to unravel the interaction and involved mechanism between Wnt4-modified NSCs and macrophages. Wnt4-modified NSCs were transplanted into SCI model to confirm the effect of Wnt4-modified NSCs on modulation of inflammatory microenvironment of SCI and the therapeutic effect of Wnt4-modified NSCs on SCI. Results: Wnt4-modified NSCs induce M2 polarization and inhibit M1 polarization of macrophages through suppress TLR4/NF-κB signal pathway; furthermore, M2 cells promote neuronal differentiation of NSCs through MAPK/JNK signal pathway. In vivo, transplantation of Wnt4-modified NSCs improve inflammatory microenvironment through induce M2 polarization and inhibit M1 polarization of macrophages to promote axonal regeneration and tissue repair.Conclusions: Transplantation of Wnt4-modified NSCs effectively improve the inflammatory microenvironment through inducing M2 polarization and suppressing M1 polarization of macrophages after SCI. Considering these positive therapeutic effects, Wnt4 may have remarkable potential to be optimal assistant agent in NSCs transplantation for SCI.