CXCL12 induces migration of oligodendrocyte precursor cells through the CXCR4‑activated MEK/ERK and PI3K/AKT pathways

Tian,Yongyang; Yin,Hong; Deng,Xi; Tang,Beichuan; Ren,Xianjun; Jiang,Tao

doi:10.3892/mmr.2018.9444

CXCL12 induces migration of oligodendrocyte precursor cells through the CXCR4‑activated MEK/ERK and PI3K/AKT pathways

Authors:
- Yongyang Tian
- Hong Yin
- Xi Deng
- Beichuan Tang
- Xianjun Ren
- Tao Jiang
View Affiliations

Affiliations: Department of Orthopedics, Third Military Medical University (Army Medical University), Chongqing 400037, P.R. China, Department of Ultrasound, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, P.R. China
Published online on: September 3, 2018 https://doi.org/10.3892/mmr.2018.9444
Pages: 4374-4380
Copyright : © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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

Demyelination is a nervous system disease in which the myelin sheaths of neurons are damaged due to inflammatory reactions, inherited abnormalities or trauma. This damage impairs the conduction of signals in the affected nerves, which in turn causes deficiencies in sensation, movement and cognition. Oligodendrocyte precursor cells (OPCs) are able to induce remyelination. However, the remyelination is suboptimal due to the limited migration of OPCs. In the present study, neonatal OPCs were isolated from rats for the investigation of the role of C‑X‑C motif chemokine ligand 12 (CXCL12), an important chemokine, in mediating the migration ability of OPCs. The present results demonstrated that CXCL12 stimulation markedly promoted the migration of OPCs and activated the dual specificity mitogen‑activated protein kinase kinase 1 (MEK)/extracellular signal‑regulated kinase (ERK) and phosphoinositide 3‑kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (AKT) pathways. Knockdown of C‑X‑C motif chemokine receptor 4 (CXCR4; a receptor of CXCL12) reversed the CXCL12‑induced migration of OPCs and blocked the MEK/ERK and PI3K/AKT pathways. In addition, specific inhibitors of the MEK/ERK and PI3K/AKT pathways significantly reduced the migration of OPCs. Based on these findings, it was concluded that CXCL12 may induce the migration of OPCs through the CXCR4‑activated MEK/ERK and PI3K/AKT pathways. The results of the present study support the manipulation of CXCL12‑mediated OPC migration to improve remyelination.

View Figures

View References

1	Nave K: Myelination and the trophic support of long axons. Nat Rev Neurosci. 11:275–283. 2010. View Article : Google Scholar : PubMed/NCBI
2	Franklin RJM ffrench-Constant C, . Regenerating CNS myelin-from mechanisms to experimental medicines. Nat Rev Neurosci. 18:753–769. 2017. View Article : Google Scholar : PubMed/NCBI
3	Young KM, Psachoulia K, Tripathi RB, Dunn SJ, Cossell L, Attwell D, Tohyama K and Richardson WD: Oligodendrocyte dynamics in the healthy adult CNS: Evidence for myelin remodeling. Neuron. 77:873–885. 2013. View Article : Google Scholar : PubMed/NCBI
4	De La Fuente AG, Lange S, Silva ME, Gonzalez GA, Tempfer H, van Wijngaarden P, Zhao C, Di Canio L, Trost A, Bieler L, et al: Pericytes stimulate oligodendrocyte progenitor cell differentiation during CNS remyelination. Cell Rep. 20:1755–1764. 2017. View Article : Google Scholar : PubMed/NCBI
5	Guo YE, Suo N, Cui X, Yuan Q and Xie X: Vitamin C promotes oligodendrocytes generation and remyelination. Glia. 66:1302–1316. 2018. View Article : Google Scholar : PubMed/NCBI
6	Alizadeh A, Dyck SM and Karimi-Abdolrezaee S: Myelin damage and repair in pathologic CNS: Challenges and prospects. Front Mol Neurosci. 8:352015. View Article : Google Scholar : PubMed/NCBI
7	Tokunaga H, Seiwa C, Yoshioka N, Mizoguchi K, Yamamoto M, Asou H and Aiso S: An extract of chinpi, the dried peel of the citrus fruit unshiu, enhances axonal remyelination via promoting the proliferation of oligodendrocyte progenitor cells. Evid Based Complement Alternat Med. 2016:86926982016. View Article : Google Scholar : PubMed/NCBI
8	Ossola B, Zhao C, Compston A, Pluchino S, Franklin RJM and Spillantini MG: Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation. Glia. 64:457–471. 2016. View Article : Google Scholar : PubMed/NCBI
9	Huang S, Tang C, Sun S, Cao W, Qi W, Xu J, Huang J, Lu W, Liu Q, Gong B, et al: Protective effect of electroacupuncture on neural myelin sheaths is mediated via promotion of oligodendrocyte proliferation and inhibition of oligodendrocyte death after compressed spinal cord injury. Mol Neurobiol. 52:1870–1881. 2015. View Article : Google Scholar : PubMed/NCBI
10	Hackett AR, Lee DH, Dawood A, Rodriguez M, Funk L, Tsoulfas P and Lee JK: STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury. Neurobiol Dis. 89:10–22. 2016. View Article : Google Scholar : PubMed/NCBI
11	Chen LX, Ma SM, Zhang P, Fan ZC, Xiong M, Cheng GQ, Yang Y, Qiu ZL, Zhou WH and Li J: Neuroprotective effects of oligodendrocyte progenitor cell transplantation in premature rat brain following hypoxic-ischemic injury. PLoS One. 10:e01159972015. View Article : Google Scholar : PubMed/NCBI
12	Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, Maherali N, Studer L, Hochedlinger K, Windrem M and Goldman SA: Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell. 12:252–264. 2013. View Article : Google Scholar : PubMed/NCBI
13	Yang J, Xiong LL, Wang YC, He X, Jiang L, Fu SJ, Han XF, Liu J and Wang TH: Oligodendrocyte precursor cell transplantation promotes functional recovery following contusive spinal cord injury in rats and is associated with altered microRNA expression. Mol Med Rep. 17:771–782. 2018.PubMed/NCBI
14	Wu B, Sun L, Li P, Tian M, Luo Y and Ren X: Transplantation of oligodendrocyte precursor cells improves myelination and promotes functional recovery after spinal cord injury. Injury. 43:794–801. 2012. View Article : Google Scholar : PubMed/NCBI
15	Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, et al: Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 4:155ra1372012. View Article : Google Scholar : PubMed/NCBI
16	Boyd A, Zhang H and Williams A: Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol. 125:841–859. 2013. View Article : Google Scholar : PubMed/NCBI
17	Janssens R, Struyf S and Proost P: The unique structural and functional features of CXCL12. Cell Mol Immunol. Oct 30–2017.(Epub ahead of print). PubMed/NCBI
18	Meng W, Xue S and Chen Y: The role of CXCL12 in tumor microenvironment. Gene. 641:105–110. 2018. View Article : Google Scholar : PubMed/NCBI
19	Kadi L, Selvaraju R, de Lys P, Proudfoot AE, Wells TN and Boschert U: Differential effects of chemokines on oligodendrocyte precursor proliferation and myelin formation in vitro. J Neuroimmunol. 174:133–146. 2006. View Article : Google Scholar : PubMed/NCBI
20	Patel JR, McCandless EE, Dorsey D and Klein RS: CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci USA. 107:11062–11067. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zilkha-Falb R, Kaushansky N, Kawakami N and Ben-Nun A: Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease. J Neuroinflammation. 13:72016. View Article : Google Scholar : PubMed/NCBI
22	Dziembowska M, Tham T, Lau P, Vitry S, Lazarini F and Dubois-Dalcq M: A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia. 50:258–269. 2005. View Article : Google Scholar : PubMed/NCBI
23	Carbajal KS, Miranda JL, Tsukamoto MR and Lane TE: CXCR4 signaling regulates remyelination by endogenous oligodendrocyte progenitor cells in a viral model of demyelination. Glia. 59:1813–1821. 2011. View Article : Google Scholar : PubMed/NCBI
24	Sobolik T, Su YJ, Wells S, Ayers GD, Cook RS and Richmond A: CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways. Mol Biol Cell. 25:566–582. 2014. View Article : Google Scholar : PubMed/NCBI
25	Kukreja P, Abdel-Mageed AB, Mondal D, Liu K and Agrawal KC: Up-regulation of CXCR4 expression in PC-3 Cells by stromal-derived factor-1α (CXCL12) increases endothelial adhesion and transendothelial migration: Role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res. 65:9891–9898. 2005. View Article : Google Scholar : PubMed/NCBI
26	Huang CY, Lee CY, Chen MY, Yang WH, Chen YH, Chang CH, Hsu HC, Fong YC and Tang CH: Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-κB-dependent pathways. J Cell Physiol. 221:204–212. 2009. View Article : Google Scholar : PubMed/NCBI
27	Armstrong R: Isolation and characterization of immature oligodendrocyte lineage cells. Armstrong RC. 16:282–292. 1998.
28	Itoh K: Culture of oligodendrocyte precursor cells (NG2+/O1-) and oligodendrocytes (NG2(−)/O1(+)) from embryonic rat cerebrum. Brain Res Brain Res Protoc. 10:23–30. 2002. View Article : Google Scholar : PubMed/NCBI
29	Yu X, Chen D, Zhang Y, Wu X, Huang Z, Zhou H, Zhang Y and Zhang Z: Overexpression of CXCR4 in mesenchymal stem cells promotes migration, neuroprotection and angiogenesis in a rat model of stroke. J Neurol Sci. 316:141–149. 2012. View Article : Google Scholar : PubMed/NCBI
30	Maysami S, Nguyen D, Zobel F, Pitz C, Heine S, Höpfner M and Stangel M: Modulation of rat oligodendrocyte precursor cells by the chemokine CXCL12. Neuroreport. 17:1187–1190. 2006. View Article : Google Scholar : PubMed/NCBI
31	Yi T, Zhai B, Yu Y, Kiyotsugu Y, Raschle T, Etzkorn M, Seo HC, Nagiec M, Luna RE, Reinherz EL, et al: Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci USA. 111:E2182–E2190. 2014. View Article : Google Scholar : PubMed/NCBI
32	Yu T, Wu Y, Helman JI, Wen Y, Wang C and Li L: CXCR4 promotes oral squamous cell carcinoma migration and invasion through inducing expression of MMP-9 and MMP-13 via the ERK signaling pathway. Mol Cancer Res. 9:161–172. 2011. View Article : Google Scholar : PubMed/NCBI
33	Sun X, Wei L, Chen Q and Terek R: CXCR4/SDF1 mediate hypoxia induced chondrosarcoma cell invasion through ERK signaling and increased MMP1 expression. Mol Cancer. 9:172010. View Article : Google Scholar : PubMed/NCBI