Anti-Inflammatory Mechanism of Neural Stem Cell Transplantation in Spinal Cord Injury.

Yi Ren,Ming Lu,Zhijian Cheng,Fei Wu,Haopen Li,Jin Li,Xijing He,Kai Cao,Guoyu Wang,Wen Zhu

doi:10.3390/ijms17091380

Abstract

Neural stem cell (NSC) transplantation has been proposed to promote functional recovery after spinal cord injury. However, a detailed understanding of the mechanisms of how NSCs exert their therapeutic plasticity is lacking. We transplanted mouse NSCs into the injured spinal cord seven days after SCI, and the Basso Mouse Scale (BMS) score was performed to assess locomotor function. The anti-inflammatory effects of NSC transplantation was analyzed by immunofluorescence staining of neutrophil and macrophages and the detection of mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-12 (IL-12). Furthermore, bone marrow-derived macrophages (BMDMs) were co-cultured with NSCs and followed by analyzing the mRNA levels of inducible nitric oxide synthase (iNOS), TNF-α, IL-1β, IL-6 and IL-10 with quantitative real-time PCR. The production of TNF-α and IL-1β by BMDMs was examined using the enzyme-linked immunosorbent assay (ELISA). Transplanted NSCs had significantly increased BMS scores (p < 0.05). Histological results showed that the grafted NSCs migrated from the injection site toward the injured area. NSCs transplantation significantly reduced the number of neutrophils and iNOS+/Mac-2+ cells at the epicenter of the injured area (p < 0.05). Meanwhile, mRNA levels of TNF-α, IL-1β, IL-6 and IL-12 in the NSCs transplantation group were significantly decreased compared to the control group. Furthermore, NSCs inhibited the iNOS expression of BMDMs and the release of inflammatory factors by macrophages in vitro (p < 0.05). These results suggest that NSC transplantation could modulate SCI-induced inflammatory responses and enhance neurological function after SCI via reducing M1 macrophage activation and infiltrating neutrophils. Thus, this study provides a new insight into the mechanisms responsible for the anti-inflammatory effect of NSC transplantation after SCI.

Highlights

Spinal cord injury (SCI) usually results in loss of functions with limited therapeutic opportunities due to demyelination, axonal damage and loss of neurons [1]
Our study showed that Neural stem cell (NSC) transplantation can create a relatively hospitable homeostasis at the injured area for tissue repair and regeneration by significantly decreasing the Messenger RNA (mRNA) level of tumor necrosis factor α (TNF-α), IL-1β, IL-6 and IL-12
Our study showed that NSCs were able to suppress the expression of the pro-inflammatory cytokine TNF-α, IL-1β, IL-6 and M1 macrophages in vivo and to reduce the expression of inducible nitric oxide synthase (iNOS), TNF-α, IL-1β and IL-6 by macrophages in vitro

Summary

Introduction

Spinal cord injury (SCI) usually results in loss of functions with limited therapeutic opportunities due to demyelination, axonal damage and loss of neurons [1]. The primary injury involves compression and/or contusion to the spinal cord resulting in tissue destruction and necrosis [2,3,4], which is followed by a cascade of pathophysiological processes hours to days later, resulting in secondary injuries, including tardive apoptosis, demyelination of surrounding neurons, the formation of glial scar and persistent inflammation [5,6]. Bone marrow-derived macrophages (BMDMs) and spinal microglia/macrophages are the major inflammatory effector cells. After being activated, they can mediate further tissue damage by producing cytotoxic factors, such as reactive nitrogen species, and pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6)

Methods

Discussion

Conclusion