Transplantation of Wnt4‐modified neural stem cells mediate M2 polarization to improve inflammatory micro‐environment of spinal cord injury

Abstract 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 micro‐environment of SCI. Previous study reported that neuroprotection and inflammatory immunomodulation were considered to be most important mechanism of NSCs transplantation. In addition, Wnt4 has been considered to be neurogenesis and anti‐inflammatory so that it would be an essential assistant agent for NSCs transplantation. Our single cells sequence indicates that macrophages are the most important contributor of inflammatory response after SCI and the interaction between macrophages and astrocytes may be the most crucial to inflammatory microenvironment of SCI. We further report the first piece of evidence to confirm the interaction between Wnt4‐modified NSCs and macrophages using NSCs‐macrophages co‐cultured system. Wnt4‐modified NSCs induce M2 polarization and inhibit M1 polarization of macrophages through suppression of 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 improves inflammatory micro‐environment through induce M2 polarization and inhibits M1 polarization of macrophages to promote axonal regeneration and tissue repair. The current study indicated that transplantation of Wnt4‐modified NSCs mediates M2 polarization of macrophages to promote spinal cord injury repair. Our novel findings would provide more insight of SCI and help with identification of novel treatment strategy.