Nerve growth factor (NGF) with hypoxia response elements loaded by adeno-associated virus (AAV) combined with neural stem cells improve the spinal cord injury recovery

Sipin Zhu,Xiaoyang Li,Qiuji Wu,Zhiyang Huang,Yurong Tu,Min Chen,Haicheng Dou,Jiahui Ye,Sunren Sheng,Ziyue Xiang,Weiyang Ying,Yibo Ying

doi:10.1038/s41420-021-00701-y

Abstract

The ischemia and hypoxia microenvironment after spinal cord injury (SCI) makes SCI repair a challenging problem. With various stimulus, chances for neural stem cells (NSCs) to differentiate into neurons, astrocytes, oligodendrocytes are great and is considered as a potential source of the stem cell therapy to SCI. Our research used adeno-associated virus (AAV) to carry the target gene to transfect neural stem cells. Transfected NSCs can express nerve growth factor (NGF) navigated by five hypoxia-responsive elements (5HRE). Therefore, the 5HRE-NGF-NSCs could express NGF specifically in hypoxia sites to promote the tissue repair and function recovery. Based on the regeneration of neurocytes and promotion of the recovery found in SCI models, via locomotor assessment, histochemical staining and molecular examinations, our results demonstrated that 5HRE-NGF-NSCs could improve the motor function, neurons survival and molecules expression of SCI rats. Meanwhile, the downregulated expression of autophagy-related proteins indicated the inhibitive effect of 5HRE-NGF-NSCs on autophagy. Our research showed that 5HRE-NGF-NSCs contribute to SCI repair which might via inhibiting autophagy and improving the survival rate of neuronal cells. The new therapy also hampered the hyperplasia of neural glial scars and induced axon regeneration. These positive functions of 5HRE-NGF-NSCs all indicate a promising SCI treatment.

Highlights

Spinal cord injury (SCI), an irreversible and devastating disease is a global health challenge for decades and lacks standard treatment [1,2,3]
Based on the regeneration of neurocytes and promotion of the recovery found in SCI models, via locomotor assessment, histochemical staining and molecular examinations, our results demonstrated that 5HRE-Neural growth factor (NGF)-Neural stem cells (NSCs) could improve the motor function, neurons survival and molecules expression of SCI rats
Our research showed that 5HRE-NGF-NSCs contribute to SCI repair which might via inhibiting autophagy and improving the survival rate of neuronal cells

Summary

Introduction

Spinal cord injury (SCI), an irreversible and devastating disease is a global health challenge for decades and lacks standard treatment [1,2,3]. Several events in secondary injury can cause neuronal death and microenvironment imbalance [6, 7]. Researches on SCI treatment mainly focus on neuron protection, axon regeneration, and angiogenesis [10,11,12]. As five hypoxia-responsive elements (5HRE) help to release NGF in hypoxia position long-lasting and the adeno-associated virus (AAV) serves as a vector, providing a platform for nutrition support and controlled expression. The AAV serves as a vector, which can provide a platform for nutrition support and controlled expression. We aimed to regulate the hypoxic microenvironment developed after injury and promote neuron survival and axon regeneration by regulating NGF expression by NSC through 5HRE [30, 31]

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