Cellular and Molecular Neurobiology

, Volume 38, Issue 4, pp 891–899 | Cite as

Ameliorating Effect of Osteopontin on H2O2-Induced Apoptosis of Human Oligodendrocyte Progenitor Cells

  • Neda Mazaheri
  • Maryam Peymani
  • Hamid Galehdari
  • Kamran GhaediEmail author
  • Ali Ghoochani
  • Abbas Kiani-Esfahani
  • Mohammad Hossein Nasr-EsfahaniEmail author
Original Research


Recently our group used oligodendrocyte progenitor cells (OPCs) as appropriate model cells to pinpoint the mechanism of the progress of neurodegenerative disorders. In the present study, we focused on the therapeutic role of osteopontin (OPN), a secreted glycosylated phosphoprotein, involved in a number of physiological events including bone formation and remodeling, immune responses, and tumor progression. Protective role of OPN, as a negative regulator of tumorigenesis, has already been clarified. Human embryonic stem cell-derived OPCs were pretreated with OPN before induction of apoptosis by H2O2. Data indicated that OPN prohibited cell death and enhanced OPC viability. This effect is achieved through reduction of apoptosis and induction of anti-apoptosis markers. In addition OPN induces expression of several integrin subunits, responsible for OPN interaction. Notably, our findings showed that expression of αV β1/β3/β5 and β8 integrins increased in response to OPN, while treatment with H2O2 down-regulated αV β1/β5 and β8 integrins expression significantly. In conclusion, OPN may act via αV integrin signaling and trigger suppression of P53-dependent apoptotic cascades. Therefore OPN therapy may be considered as a feasible process to prevent progress of neurodegenerative diseases in human.


OPC OPN H2O2 Apoptosis 



One-way analysis of variance


Basic fibroblast growth factor


Central nervous system


Embryoid bodies


Extracellular matrix


Epidermal growth factor


Fluorescein isothiocyanate


Human embryonic stem cell




Myelin basic protein


Multiple sclerosis




Oligodendrocyte progenitor cells




Phosphate-buffered saline


Platelet-derived growth factor




Retinoic acid




Reactive oxygen species


Real-time quantitative PCR


Standard error of mean


Tetramethyl rhodamine isothiocyanate



We thank our colleagues for their association and helpful discussions in this study.

Author Contributions

NM was involved in concept and design, acquisition, analysis and interpretation of data, and drafting of the manuscript. MP was involved in supervision, and contributed to the design of work, analysis, and interpretation of data, and drafted sections of manuscript. HG was involved in supervision and contributed to design of work. KG was involved in supervision, and contributed to the design of work, analysis, and interpretation of data, critical revision of the manuscript for important intellectual content, and finalized the manuscript. AG contributed to design the work. AKE was involved in acquisition of data and drafted sections of manuscript. MHNE was involved in supervision, and contributed to the design of work, administrative, technical, or material support.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Albertsson AM, Zhang X, Leavenworth J, Bi D, Nair S, Qiao L, Hagberg H, Mallard C, Cantor H, Wang X (2014) The effect of osteopontin and osteopontin-derived peptides on preterm brain injury. J Neuroinflamm 11:197CrossRefGoogle Scholar
  2. Baud O, Greene AE, Li J, Wang H, Volpe JJ, Rosenberg PA (2004) Glutathione peroxidase-catalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes. J Neurosci 24:1531–1540CrossRefPubMedGoogle Scholar
  3. Behera R, Kumar V, Lohite K, Karnik S, Kundu GC (2009) Activation of JAK2/STAT3 signaling by osteopontin promotes tumor growth in human breast cancer cells. Carcinogenesis 31:192–200CrossRefPubMedGoogle Scholar
  4. Buchet D, Baron-Van Evercooren A (2009) In search of human oligodendroglia for myelin repair. Neurosci Lett 456:112–119CrossRefPubMedGoogle Scholar
  5. Burdo TH, Wood MR, Fox HS (2007) Osteopontin prevents monocyte recirculation and apoptosis. J Leukoc Biol 81:1504–1511CrossRefPubMedPubMedCentralGoogle Scholar
  6. Dash P (1994) Apoptosis; basic medical sciences. St.George’s University of London, LondonGoogle Scholar
  7. Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS (2001) Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107:1055CrossRefPubMedPubMedCentralGoogle Scholar
  8. Dhib-Jalbut S (2007) Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology 68:S13–S21CrossRefPubMedGoogle Scholar
  9. Geissinger E, Weisser C, Fischer P, Schartl M, Wellbrock C (2002) Autocrine stimulation by osteopontin contributes to antiapoptotic signalling of melanocytes in dermal collagen. Cancer Res 62:4820–4828PubMedGoogle Scholar
  10. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hirrlinger J, Resch A, Gutterer JM, Dringen R (2002) Oligodendroglial cells in culture effectively dispose of exogenous hydrogen peroxide: comparison with cultured neurones, astroglial and microglial cells. J Neuroche 82:635–644CrossRefGoogle Scholar
  12. Hsu KH, Tsai HW, Lin PW, Hsu YS, Lu PJ, Shan YS (2014) Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors. World J Surg Oncol 12:189CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hur EM, Youssef S, Haws ME, Zhang SY, Sobel RA, Steinman L (2007) Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol 8:74–83CrossRefPubMedGoogle Scholar
  14. Kajabadi NS, Ghoochani A, Peymani M, Ghaedi K, Kiani-Esfahani A, Hashemi MS, Nasr-Esfahani MH, Baharvand H (2015) The synergistic enhancement of cloning efficiency in individualized human pluripotent stem cells by peroxisome proliferative-activated receptor-γ (PPARγ) activation and rho-associated kinase (ROCK) inhibition. J Biol Chem 290(43):26303–26313CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kanduc D, Mittelman A, Serpico R, Sinigaglia E, Sinha AA, Natale C, Santacroce R, Di Corcia MG, Lucchese A, Dini L, Pani P, Santacroce S, Simone S, Bucci R, Farber E (2002) Cell death: apoptosis versus necrosis. Int J Oncol 21:165–170PubMedGoogle Scholar
  16. Kim HJ, Lee HJ, Jun JI, Oh Y, Choi SG, Kim H, Chung CW, Kim IK, Park IS, Chae HJ, Kim HR, Jung YK (2009) Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53. Proc Natl Acad Sci U S A 106(36):15326–15331CrossRefPubMedPubMedCentralGoogle Scholar
  17. Merrill J, Pu S.-F, Khorkova O, Ji Z, Camacho F, Busch S, Wang M, Chen T, Dinerstein, R, Yao Z (2003) Osteopontin, oligodendrocytes and myelination. Google PatentsGoogle Scholar
  18. Milner R, Ffrench-Constant C (1994) A developmental analysis of oligodendroglial integrins in primary cells: changes in alpha v-associated beta subunits during differentiation. Development 120:3497–3506PubMedGoogle Scholar
  19. Miron VE, Kuhlmann T, Antel JP (2011) Cells of the oligodendroglial lineage, myelination, and remyelination. Biochim Biophys Acta 1812:184–193CrossRefPubMedGoogle Scholar
  20. Mouzannar R, Miric SJ, Wiggins RC, Konat GW (2001) Hydrogen peroxide induces rapid digestion of oligodendrocyte chromatin into high molecular weight fragments. Neurochem Int 38:9–15CrossRefPubMedGoogle Scholar
  21. O’Meara RW, Michalski JP, Kothary R (2010) Integrin signaling in oligodendrocytes and its importance in CNS myelination. J Signal Transduct 2011:354091PubMedPubMedCentralGoogle Scholar
  22. Peymani M, Ghaedi K, Hashemi MS, Ghoochani A, Kiani-Esfahani A, Nasr-Esfahani MH, Baharvand H (2017) Ameliorating the effect of pioglitazone on LPS-induced inflammation of human oligodendrocyte progenitor cells. Cell Mol Neurobiol. Google Scholar
  23. Polager S, Ginsberg D (2009) p53 and E2f: partners in life and death. Nat Rev Cancer 9:738–748CrossRefPubMedGoogle Scholar
  24. Pouya A, Satarian L, Kiani S, Javan M, Baharvand H (2011) Human induced pluripotent stem cells differentiation into oligodendrocyte progenitors and transplantation in a rat model of optic chiasm demyelination. PLoS ONE 6:e27925CrossRefPubMedPubMedCentralGoogle Scholar
  25. Rabenstein M, Hucklenbroich J, Willuweit A, Ladwig A, Fink GR, Schroeter M, Langen KJ, Rueger MA (2015) Osteopontin mediates survival, proliferation and migration of neural stem cells through the chemokine receptor CXCR4. Stem Cell Res Ther 6:99CrossRefPubMedPubMedCentralGoogle Scholar
  26. Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM (1998) NF-κB mediates αvβ3 integrin-induced endothelial cell survival. J Cell Biol 141:1083–1093CrossRefPubMedPubMedCentralGoogle Scholar
  27. Schordan S, Schordan E, Endlich K, Endlich N (2011) α V-Integrins mediate the mechanoprotective action of osteopontin in podocytes. Am J Physiol Renal Physiol 300:F119–F132CrossRefPubMedGoogle Scholar
  28. Selvaraju R, Bernasconi L, Losberger C, Graber P, Kadi L, Avellana-Adalid V, Picard-Riera N, Baron Van Evercooren A, Cirillo R, Kosco-Vilbois M, Feger G, Papoian R, Boschert U (2004) Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro. Mol Cell Neurosci 25:707–721CrossRefPubMedGoogle Scholar
  29. Sodek J, Ganss B, McKee MD (2000) Osteopontin. Crit Rev Oral Biol Med 11:279–303CrossRefPubMedGoogle Scholar
  30. Song G, Ming Y, Mao Y, Bao S, Ouyang G (2008) Osteopontin prevents curcumin-induced apoptosis and promotes survival through Akt activation via αvβ3 integrins in human gastric cancer cells. Exp Biol Med 233:1537–1545CrossRefGoogle Scholar
  31. Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10:712–723CrossRefPubMedGoogle Scholar
  32. Stangel M, Hartung HP (2002) Remyelinating strategies for the treatment of multiple sclerosis. Prog Neurobio 68:361–376CrossRefGoogle Scholar
  33. Watzlawik J, Warrington AE, Rodriguez M (2010) Importance of oligodendrocyte protection, BBB breakdown and inflammation for remyelination. Expert Rev Neurother 10:441–457CrossRefPubMedPubMedCentralGoogle Scholar
  34. Wittmann C, Chockley P, Singh SK, Pase L, Lieschke GJ, Grabher C (2012) Hydrogen peroxide in inflammation: messenger, guide, and assassin. Adv Hematol 2012:541471CrossRefPubMedPubMedCentralGoogle Scholar
  35. Zahed Panah M, Nikbakht M, Sajjadi SM, Rostami S, Norooznezhad AH, Kamranzadeh Fumani H, Ghavamzadeh A, Mohammadi S (2017) Anti-apoptotic effects of osteopontin via the up-regulation of AKT/mTOR/β-catenin loop in acute myeloid leukemia cells. Int J Hematol Oncol Stem Cell Res 11(2):148–157PubMedPubMedCentralGoogle Scholar
  36. Zhao C, Fancy SP, French-Constant C, Franklin RJ (2008) Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination. Neurobiol Dis 31:209–217CrossRefPubMedGoogle Scholar
  37. Zhao C, Fancy SP, Franklin RJ, French-Constant C (2009) Up-regulation of oligodendrocyte precursor cell αV integrin and its extracellular ligands during central nervous system remyelination. J Neurosci Res 87:3447–3455CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Neda Mazaheri
    • 1
  • Maryam Peymani
    • 2
    • 4
  • Hamid Galehdari
    • 1
  • Kamran Ghaedi
    • 3
    • 4
    Email author
  • Ali Ghoochani
    • 4
  • Abbas Kiani-Esfahani
    • 4
  • Mohammad Hossein Nasr-Esfahani
    • 3
    • 4
    Email author
  1. 1.Department of Genetics, Faculty of ScienceShahid Chamran University of AhvazAhvazIran
  2. 2.Department of Biology, Faculty of Basic Sciences, Shahrekord BranchIslamic Azad UniversityShahrekordIran
  3. 3.Department of Biology, Faculty of SciencesUniversity of IsfahanIsfahanIran
  4. 4.Department of Cellular Biotechnology, Cell Science Research CenterRoyan Institute for Biotechnology, ACECRIsfahanIran

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