The repair and autophagy mechanisms of hypoxia-regulated bFGF-modified primary embryonic neural stem cells in spinal cord injury.

Sipin Zhu,Xiaokun Li,Jinjing Zhang,Liancheng Deng,Jiake Xu,Felix Yao,Huazi Xu,Wenfei Ni,Min Chen,Jian Xiao,Xiangyang Wang

doi:10.1002/sctm.19-0282

Abstract

There is no effective strategy for the treatment of spinal cord injury (SCI), a devastating condition characterized by severe hypoxia and ischemic insults. In this study, we investigated the histology and pathophysiology of the SCI milieu in a rat model and found that areas of hypoxia were unevenly interspersed in compressed SCI. With this new knowledge, we generated embryonic neural stem cells (NSCs) expressing basic fibroblast growth factor (bFGF) under the regulation of five hypoxia‐responsive elements (5HRE) using a lentiviral vector (LV‐5HRE‐bFGF‐NSCs) to specifically target these hypoxic loci. SCI models treated with bFGF expressed by the LV‐5HRE‐bFGF‐NSCs viral vector demonstrated improved recovery, increased neuronal survival, and inhibited autophagy in spinal cord lesions in the rat model due to the reversal of hypoxic conditions at day 42 after injury. Furthermore, improved functional restoration of SCI with neuron regeneration was achieved in vivo, accompanied by glial scar inhibition and the evidence of axon regeneration across the scar boundary. This is the first study to illustrate the presence of hypoxic clusters throughout the injury site of compressed SCI and the first to show that the transplantation of LV‐5HRE‐bFGF‐NSCs to target this hypoxic microenvironment enhanced the recovery of neurological function after SCI in rats; LV‐5HRE‐bFGF‐NSCs may therefore be a good candidate to evaluate cellular SCI therapy in humans.

Highlights

Spinal cord injury (SCI) is a devastating event that usually results in significant functional impairment in the patient
The expression patterns of hypoxia-inducible factor-1α (HIF-1α), a transacting factor widely expressed in ischemia, were studied at the mRNA and protein levels, and we discovered a pattern of hypoxia with increased cell autophagy throughout the injured spinal cord.[17]
Our study shows that the application of LV-5HRE-bFGFNSCs to target these hypoxic loci reversed the hypoxic microenvironment at day 60 after spinal cord injury (SCI), concomitant with decreased cellular autophagy, reduced central nervous system (CNS) glial scar formation, and improved locomotor function in in vivo studies

Summary

| INTRODUCTION

Spinal cord injury (SCI) is a devastating event that usually results in significant functional impairment in the patient. The present study shows that application of hypoxiaregulated basic fibroblast growth factor modified primary embryonic neural stem cells to target the hypoxic loci resulted in a reversal of the hypoxic microenvironment after spinal cord injury (SCI), concomitant with decreased cellular autophagy, reduced CNS glial scar formation, and improved locomotor function in in vivo studies. The results of the present study increase the current understanding of the pathophysiology of SCI and may be used to combat the ischemic microenvironment that can induce cell death and limit cell transplantation approaches to promote spinal cord regeneration. The results of this study increase the current understanding of the pathophysiology of SCI and may be employed to combat the ischemic microenvironment, which can induce cell death and limit cell transplantation approaches, to promote spinal cord regeneration

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION

| CONCLUSION