Transplantation of neural stem cells preconditioned with high‑mobility group box 1 facilitates functional recovery after spinal cord injury in rats

Xue,Xin; Zhang,Liang; Yin,Xiang; Chen,Xing‑Xing; Chen,Zong‑Feng; Wang,Chen‑Xu; Xiang,Yu; Liu,Ming‑Yong; Zhao,Jian‑Hua

doi:10.3892/mmr.2020.11565

Transplantation of neural stem cells preconditioned with high‑mobility group box 1 facilitates functional recovery after spinal cord injury in rats

Authors:
- Xin Xue
- Liang Zhang
- Xiang Yin
- Xing‑Xing Chen
- Zong‑Feng Chen
- Chen‑Xu Wang
- Yu Xiang
- Ming‑Yong Liu
- Jian‑Hua Zhao
View Affiliations

Affiliations: Department of Spinal Surgery, Daping Hospital, Research Institute of Surgery, Third Military Medical University (Army Medical University), Chongqing 400042, P.R. China, Department of Spinal Surgery, Daping Hospital, Research Institute of Surgery, Third Military Medical University (Army Medical University), Chongqing 400042, P.R. China, Department of Orthopedic, No. 517 Hospital of People's Liberation Army, Xinzhou, Shanxi 030002, P.R. China
Published online on: October 6, 2020 https://doi.org/10.3892/mmr.2020.11565
Pages: 4725-4733
Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Spinal cord injury (SCI) is a devastating disorder that often results in temporary and/or permanent functional impairment below the injured level. To date, few satisfactory therapeutic strategies are available to treat SCI. Hence, exploring novel strategies for SCI is an essential public health concern. Cell transplantation therapy, which is associated with neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration, provides a promising therapeutic strategy for SCI. The neuronal stem cell (NSC) preconditioning method is an emerging approach, which facilitates NSC survival and neuronal differentiation after implantation. The aim of the present study was to develop a feasible candidate for cell‑based therapy following SCI in rats and to investigate the role of high mobility group box‑1 (HMGB1) in NSC activation. The results of the present study showed that transplantation of NSCs, preconditioned with 1 ng/ml HMGB1, facilitated functional improvement of injured spinal cords, as indicated by Basso, Beattie and Bresnahan mean scores, mechanical hypersensitivity and cold stimulation. Meanwhile, the histological examination of hematoxylin and eosin staining indicated that engraftment of HMGB1‑preconditioned NSCs resulted in decreased atrophy of the injured spinal cord. Meanwhile, the transplantation of HMGB1‑preconditioned NSCs resulted in an increased number of functional Nissl bodies in neurons, as detected by Nissl staining, and an increase in the number of βIII‑tubulin+ cells in the epicenter of injured spinal cords in rats with SCI. In addition, the results also demonstrated that 1 ng/ml HMGB1 promoted the differentiation of NSCs into neurons, and that the ERK signaling pathway played an important role in this process. In conclusion, the present data indicated that the preconditioning strategy with 1 ng/ml HMGB1 may present a feasible candidate for cell‑based therapy following SCI in rats, which may enlarge the scope of HMGB1 in NSC activation.

View Figures

View References

1	Li X, Liu D, Xiao Z, Zhao Y, Han S, Chen B and Dai J: Scaffold-facilitated locomotor improvement post complete spinal cord injury: Motor axon regeneration versus endogenous neuronal relay formation. Biomaterials. 197:20–31. 2019. View Article : Google Scholar : PubMed/NCBI
2	Fan WL, Liu P, Wang G, Pu JG, Xue X and Zhao JH: Transplantation of hypoxic preconditioned neural stem cells benefits functional recovery via enhancing neurotrophic secretion after spinal cord injury in rats. J Cell Biochem. 119:4339–4351. 2018. View Article : Google Scholar : PubMed/NCBI
3	Vismara I, Papa S, Rossi F, Forloni G and Veglianese P: Current options for cell therapy in spinal cord injury. Trends Mol Med. 23:831–849. 2017. View Article : Google Scholar : PubMed/NCBI
4	Upadhyay G, Shankar S and Srivastava RK: Stem cells in neurological disorders: Emerging therapy with stunning hopes. Mol Neurobiol. 52:610–625. 2015. View Article : Google Scholar : PubMed/NCBI
5	Assinck P, Duncan GJ, Hilton BJ, Plemel JR and Tetzlaff W: Cell transplantation therapy for spinal cord injury. Nat Neurosci. 20:637–647. 2017. View Article : Google Scholar : PubMed/NCBI
6	Jin H, Zhang YT, Yang Y, Wen LY, Wang JH, Xu HY, Lai BQ, Feng B, Che MT, Qiu XC, et al: Electroacupuncture facilitates the integration of neural stem cell-derived neural network with transected rat spinal cord. Stem Cell Reports. 12:274–289. 2019. View Article : Google Scholar : PubMed/NCBI
7	Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, Moghadas Jafari A, Asady H, Razavi Tousi SMT and Hosseini M: Neural stem/progenitor cell transplantation for spinal cord injury treatment; A systematic review and meta-analysis. Neuroscience. 322:377–397. 2016. View Article : Google Scholar : PubMed/NCBI
8	Karova K, Wainwright JV, Machova-Urdzikova L, Pisal RV, Schmidt M, Jendelova P and Jhanwar-Uniyal M: Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-βB pathway inhibition. J Neuroinflammation. 16:122019. View Article : Google Scholar : PubMed/NCBI
9	Kojima K, Miyoshi H, Nagoshi N, Kohyama J, Itakura G, Kawabata S, Ozaki M, Iida T, Sugai K, Ito S, et al: Selective ablation of tumorigenic cells following human induced pluripotent stem cell-derived neural stem/progenitor cell transplantation in spinal cord injury. Stem Cells Transl Med. 8:260–270. 2019. View Article : Google Scholar : PubMed/NCBI
10	Hooshmand MJ, Sontag CJ, Uchida N, Tamaki S, Anderson AJ and Cummings BJ: Analysis of host-mediated repair mechanisms after human CNS-stem cell transplantation for spinal cord injury: Correlation of engraftment with recovery. PLoS One. 4:e58712009. View Article : Google Scholar : PubMed/NCBI
11	Babu H, Cheung G, Kettenmann H, Palmer TD and Kempermann G: Enriched monolayer precursor cell cultures from micro-dissected adult mouse dentate gyrus yield functional granule cell-like neurons. PLoS One. 2:e3882007. View Article : Google Scholar : PubMed/NCBI
12	Ronaghi M, Erceg S, Moreno-Manzano V and Stojkovic M: Challenges of stem cell therapy for spinal cord injury: Human embryonic stem cells, endogenous neural stem cells, or induced pluripotent stem cells? Stem Cells. 28:93–99. 2010.PubMed/NCBI
13	Xue X, Chen X, Fan W, Wang G, Zhang L, Chen Z, Liu P, Liu M and Zhao J: High-mobility group box 1 facilitates migration of neural stem cells via receptor for advanced glycation end products signaling pathway. Sci Rep. 8:45132018. View Article : Google Scholar : PubMed/NCBI
14	Ge H, Tan L, Wu P, Yin Y, Liu X, Meng H, Cui G, Wu N, Lin J, Hu R and Feng H: Poly-L-ornithine promotes preferred differentiation of neural stem/progenitor cells via ERK signalling pathway. Sci Rep. 5:155352015. View Article : Google Scholar : PubMed/NCBI
15	Basso DM, Beattie MS and Bresnahan JC: Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol. 139:244–256. 1996. View Article : Google Scholar : PubMed/NCBI
16	Jurga AM, Rojewska E, Piotrowska A, Makuch W, Pilat D, Przewlocka B and Mika J: Blockade of toll-like receptors (TLR2, TLR4) attenuates pain and potentiates buprenorphine analgesia in a rat neuropathic pain model. Neural Plast. 2016:52387302016. View Article : Google Scholar : PubMed/NCBI
17	Hu R, Zhou J, Luo C, Lin J, Wang X, Li X, Bian X, Li Y, Wan Q, Yu Y and Feng H: Glial scar and neuroregeneration: Histological, functional, and magnetic resonance imaging analysis in chronic spinal cord injury. J Neurosurg Spine. 13:169–180. 2010. View Article : Google Scholar : PubMed/NCBI
18	Liu H, Zhou J, Gu L and Zuo Y: The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy. Oncotarget. 8:1110–1116. 2017. View Article : Google Scholar : PubMed/NCBI
19	Paudel YN, Semple BD, Jones NC, Othman I and Shaikh MF: High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: From pathogenesis to therapeutic approaches. J Neurochem. 151:542–557. 2019. View Article : Google Scholar : PubMed/NCBI
20	Hei Y, Chen R, Yi X, Long Q, Gao D and Liu W: HMGB1 neutralization attenuates hippocampal neuronal death and cognitive impairment in rats with chronic cerebral hypoperfusion via suppressing inflammatory responses and oxidative stress. Neuroscience. 383:150–159. 2018. View Article : Google Scholar : PubMed/NCBI
21	Uezono N, Zhu Y, Fujimoto Y, Yasui T, Matsuda T, Nakajo M, Abematsu M, Setoguchi T, Mori S, Takahashi HK, et al: Prior treatment with anti-high mobility group box-1 antibody boosts human neural stem cell transplantation-mediated functional recovery after spinal cord injury. Stem Cells. 36:737–750. 2018. View Article : Google Scholar : PubMed/NCBI
22	Wang H, Mei X, Cao Y, Liu C, Zhao Z, Guo Z, Bi Y, Shen Z, Yuan Y, Guo Y, et al: HMGB1/advanced glycation end products (RAGE) does not aggravate inflammation but promote endogenous neural stem cells differentiation in spinal cord injury. Sci Rep. 7:103322017. View Article : Google Scholar : PubMed/NCBI
23	Tirone M, Tran NL, Ceriotti C, Gorzanelli A, Canepari M, Bottinelli R, Raucci A, Di Maggio S, Santiago C, Mellado M, et al: High mobility group box 1 orchestrates tissue regeneration via CXCR4. J Exp Med. 215:303–318. 2018. View Article : Google Scholar : PubMed/NCBI
24	Lei C, Lin S, Zhang C, Tao W, Dong W, Hao Z, Liu M and Wu B: Effects of high-mobility group box1 on cerebral angiogenesis and neurogenesis after intracerebral hemorrhage. Neuroscience. 229:12–19. 2013. View Article : Google Scholar : PubMed/NCBI
25	Wang L, Yu L, Zhang T, Wang L, Leng Z, Guan Y and Wang X: HMGB1 enhances embryonic neural stem cell proliferation by activating the MAPK signaling pathway. Biotechnol Lett. 36:1631–1639. 2014. View Article : Google Scholar : PubMed/NCBI
26	Meneghini V, Bortolotto V, Francese MT, Dellarole A, Carraro L, Terzieva S and Grilli M: High-mobility group box-1 protein and β-amyloid oligomers promote neuronal differentiation of adult hippocampal neural progenitors via receptor for advanced glycation end products/nuclear factor-κB axis: Relevance for Alzheimer's disease. J Neurosci. 33:6047–6059. 2013. View Article : Google Scholar : PubMed/NCBI