PMID- 33723238 OWN - NLM STAT- MEDLINE DCOM- 20210913 LR - 20240226 IS - 2041-4889 (Electronic) VI - 12 IP - 3 DP - 2021 Mar 15 TI - AAV2-mediated and hypoxia response element-directed expression of bFGF in neural stem cells showed therapeutic effects on spinal cord injury in rats. PG - 274 LID - 10.1038/s41419-021-03546-6 [doi] LID - 274 AB - Neural stem cell (NSCs) transplantation has been one of the hot topics in the repair of spinal cord injury (SCI). Fibroblast growth factor (FGF) is considered a promising nerve injury therapy after SCI. However, owing to a hostile hypoxia condition in SCI, there remains a challenging issue in implementing these tactics to repair SCI. In this report, we used adeno-associated virus 2 (AAV2), a prototype AAV used in clinical trials for human neuron disorders, basic FGF (bFGF) gene under the regulation of hypoxia response element (HRE) was constructed and transduced into NSCs to yield AAV2-5HRE-bFGF-NSCs. Our results showed that its treatment yielded temporally increased expression of bFGF in SCI, and improved scores of functional recovery after SCI compared to vehicle control (AAV2-5HRE-NSCs) based on the analyses of the inclined plane test, Basso-Beattie-Bresnahan (BBB) scale and footprint analysis. Mechanistic studies showed that AAV2-5HRE-bFGF-NSCs treatment increased the expression of neuron-specific neuronal nuclei protein (NeuN), neuromodulin GAP43, and neurofilament protein NF200 while decreased the expression of glial fibrillary acidic protein (GFAP) as compared to the control group. Further, the expressions of autophagy-associated proteins LC3-II and Beclin 1 were decreased, whereas the expression of P62 protein was increased in AAV2-5HRE-bFGF-NSCs treatment group. Taken together, our data indicate that AAV2-5HRE-bFGF-NSCs treatment improved the recovery of SCI rats, which is accompanied by evidence of nerve regeneration, and inhibition of SCI-induced glial scar formation and cell autophagy. Thus, this study represents a step forward towards the potential use of AAV2-5HRE-bFGF-NSCs for future clinical trials of SCI repair. FAU - Zhu, Sipin AU - Zhu S AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. sipinzhu@163.com. AD - The Second School of Medicine, Wenzhou Medical University, 325027, Wenzhou, China. sipinzhu@163.com. AD - School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia. sipinzhu@163.com. FAU - Ying, Yibo AU - Ying Y AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. AD - The Second School of Medicine, Wenzhou Medical University, 325027, Wenzhou, China. FAU - Ye, Jiahui AU - Ye J AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. AD - The Second School of Medicine, Wenzhou Medical University, 325027, Wenzhou, China. FAU - Chen, Min AU - Chen M AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. AD - The Second School of Medicine, Wenzhou Medical University, 325027, Wenzhou, China. FAU - Wu, Qiuji AU - Wu Q AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. AD - The Second School of Medicine, Wenzhou Medical University, 325027, Wenzhou, China. FAU - Dou, Haicheng AU - Dou H AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. FAU - Ni, Wenfei AU - Ni W AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. FAU - Xu, Huazi AU - Xu H AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. FAU - Xu, Jiake AU - Xu J AUID- ORCID: 0000-0003-2021-8309 AD - School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia. jiake.xu@uwa.edu.au. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210315 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Autophagy-Related Proteins) RN - 0 (Nerve Tissue Proteins) RN - 103107-01-3 (Fibroblast Growth Factor 2) RN - Adeno-associated virus-2 SB - IM MH - Animals MH - Autophagy MH - Autophagy-Related Proteins/metabolism MH - Cell Hypoxia MH - Cells, Cultured MH - Dependovirus/*genetics MH - Disease Models, Animal MH - Fibroblast Growth Factor 2/*biosynthesis/genetics MH - Gene Transfer Techniques MH - *Genetic Therapy MH - *Genetic Vectors MH - *Nerve Regeneration MH - Nerve Tissue Proteins/metabolism MH - Neural Stem Cells/metabolism/*transplantation MH - Neuroglia/metabolism/pathology MH - Rats, Sprague-Dawley MH - Recovery of Function MH - *Response Elements MH - Spinal Cord/metabolism/pathology/*physiopathology MH - Spinal Cord Injuries/genetics/metabolism/physiopathology/*therapy MH - Rats PMC - PMC7960741 COIS- The authors declare no competing interests. EDAT- 2021/03/17 06:00 MHDA- 2021/09/14 06:00 PMCR- 2021/03/15 CRDT- 2021/03/16 06:22 PHST- 2020/11/30 00:00 [received] PHST- 2021/02/10 00:00 [accepted] PHST- 2021/02/08 00:00 [revised] PHST- 2021/03/16 06:22 [entrez] PHST- 2021/03/17 06:00 [pubmed] PHST- 2021/09/14 06:00 [medline] PHST- 2021/03/15 00:00 [pmc-release] AID - 10.1038/s41419-021-03546-6 [pii] AID - 3546 [pii] AID - 10.1038/s41419-021-03546-6 [doi] PST - epublish SO - Cell Death Dis. 2021 Mar 15;12(3):274. doi: 10.1038/s41419-021-03546-6.