Mitochondrial Neuroglobin Is Necessary for Protection Induced by Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells in Astrocytic Cells Subjected to Scratch and Metabolic Injury

Abstract

Astrocytes are specialized cells capable of regulating inflammatory responses in neurodegenerative diseases or traumatic brain injury. In addition to playing an important role in neuroinflammation, these cells regulate essential functions for the preservation of brain tissue. Therefore, the search for therapeutic alternatives to preserve these cells and maintain their functions contributes in some way to counteract the progress of the injury and maintain neuronal survival in various brain pathologies. Among these strategies, the conditioned medium from human adipose-derived mesenchymal stem cells (CM-hMSCA) has been reported with a potential beneficial effect against several neuropathologies. In this study, we evaluated the potential effect of CM-hMSCA in a model of human astrocytes (T98G cells) subjected to scratch injury. Our findings demonstrated that CM-hMSCA regulates the cytokines IL-2, IL-6, IL-8, IL-10, GM-CSF, and TNF-α, downregulates calcium at the cytoplasmic level, and regulates mitochondrial dynamics and the respiratory chain. These actions are accompanied by modulation of the expression of different proteins involved in signaling pathways such as AKT/pAKT and ERK1/2/pERK, and may mediate the localization of neuroglobin (Ngb) at the cellular level. We also confirmed that Ngb mediated the protective effects of CM-hMSCA through regulation of proteins involved in survival pathways and oxidative stress. In conclusion, regulation of brain inflammation combined with the recovery of fundamental cellular aspects in the face of injury makes CM-hMSCA a promising candidate for the protection of astrocytes in brain pathologies.

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References

  1. 1.

    Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13(4):3391–3396. https://doi.org/10.3892/mmr.2016.4948

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Gonzalez H, Elgueta D, Montoya A, Pacheco R (2014) Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 274(1–2):1–13. https://doi.org/10.1016/j.jneuroim.2014.07.012

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, Hardy J, Pocock JM (2016) Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease. Curr Opin Neurobiol 36:74–81. https://doi.org/10.1016/j.conb.2015.10.004

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Karve IP, Taylor JM, Crack PJ (2016) The contribution of astrocytes and microglia to traumatic brain injury. Br J Pharmacol 173(4):692–702. https://doi.org/10.1111/bph.13125

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Sochocka M, Diniz BS, Leszek J (2017) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54(10):8071–8089. https://doi.org/10.1007/s12035-016-0297-1

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Pedraza-Alva G, Perez-Martinez L, Valdez-Hernandez L, Meza-Sosa KF, Ando-Kuri M (2015) Negative regulation of the inflammasome: keeping inflammation under control. Immunol Rev 265(1):231–257. https://doi.org/10.1111/imr.12294

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ulusoy C, Zibandeh N, Yildirim S, Trakas N, Zisimopoulou P, Kucukerden M, Tasli H, Tzartos S et al (2015) Dental follicle mesenchymal stem cell administration ameliorates muscle weakness in MuSK-immunized mice. J Neuroinflammation 12:231. https://doi.org/10.1186/s12974-015-0451-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Trubiani O, Giacoppo S, Ballerini P, Diomede F, Piattelli A, Bramanti P, Mazzon E (2016) Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis. Stem Cell Res Ther 7:1. https://doi.org/10.1186/s13287-015-0253-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Baez-Jurado E, Hidalgo-Lanussa O, Guio-Vega G, Ashraf GM, Echeverria V, Aliev G, Barreto GE (2018) Conditioned medium of human adipose mesenchymal stem cells increases wound closure and protects human astrocytes following scratch assay in vitro. Mol Neurobiol 55(6):5377–5392. https://doi.org/10.1007/s12035-017-0771-4

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Baez-Jurado E, Vega GG, Aliev G, Tarasov VV, Esquinas P, Echeverria V, Barreto GE (2018) Blockade of neuroglobin reduces protection of conditioned medium from human mesenchymal stem cells in human astrocyte model (T98G) under a scratch assay. Mol Neurobiol 55(3):2285–2300. https://doi.org/10.1007/s12035-017-0481-y

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R (2016) The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy 18(1):13–24. https://doi.org/10.1016/j.jcyt.2015.10.008

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Guillen MI, Platas J, Perez Del Caz MD, Mirabet V, Alcaraz MJ (2018) Paracrine anti-inflammatory effects of adipose tissue-derived mesenchymal stem cells in human monocytes. Front Physiol 9:661. https://doi.org/10.3389/fphys.2018.00661

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Guo ZY, Sun X, Xu XL, Zhao Q, Peng J, Wang Y (2015) Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen Res 10(4):651–658. https://doi.org/10.4103/1673-5374.155442

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mita T, Furukawa-Hibi Y, Takeuchi H, Hattori H, Yamada K, Hibi H, Ueda M, Yamamoto A (2015) Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer's disease. Behav Brain Res 293:189–197. https://doi.org/10.1016/j.bbr.2015.07.043

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Pischiutta F, Brunelli L, Romele P, Silini A, Sammali E, Paracchini L, Marchini S, Talamini L et al (2016) Protection of brain injury by amniotic mesenchymal stromal cell-secreted metabolites. Crit Care Med 44(11):e1118–e1131. https://doi.org/10.1097/CCM.0000000000001864

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Mekhemar MK, Adam-Klages S, Kabelitz D, Dorfer CE, Fawzy El-Sayed KM (2018) TLR-induced immunomodulatory cytokine expression by human gingival stem/progenitor cells. Cell Immunol 326:60–67. https://doi.org/10.1016/j.cellimm.2017.01.007

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Fawzy El-Sayed KM, Dorfer CE (2016) Gingival mesenchymal stem/progenitor cells: a unique tissue engineering gem. Stem Cells Int 2016:7154327–7154316. https://doi.org/10.1155/2016/7154327

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Torrente D, Avila MF, Cabezas R, Morales L, Gonzalez J, Samudio I, Barreto GE (2014) Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model. Hum Exp Toxicol 33(7):673–684. https://doi.org/10.1177/0960327113509659

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Song M, Jue SS, Cho YA, Kim EC (2015) Comparison of the effects of human dental pulp stem cells and human bone marrow-derived mesenchymal stem cells on ischemic human astrocytes in vitro. J Neurosci Res 93(6):973–983. https://doi.org/10.1002/jnr.23569

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Huang W, Lv B, Zeng H, Shi D, Liu Y, Chen F, Li F, Liu X et al (2015) Paracrine factors secreted by MSCs promote astrocyte survival associated with GFAP downregulation after ischemic stroke via p38 MAPK and JNK. J Cell Physiol 230(10):2461–2475. https://doi.org/10.1002/jcp.24981

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Sun H, Benardais K, Stanslowsky N, Thau-Habermann N, Hensel N, Huang D, Claus P, Dengler R et al (2013) Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in amyotrophic lateral sclerosis (ALS)—in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia. PLoS One 8(9):e72926. https://doi.org/10.1371/journal.pone.0072926

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Baez E, Echeverria V, Cabezas R, Avila-Rodriguez M, Garcia-Segura LM, Barreto GE (2016) Protection by neuroglobin expression in brain pathologies. Front Neurol 7:146. https://doi.org/10.3389/fneur.2016.00146

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Amri F, Ghouili I, Amri M, Carrier A, Masmoudi-Kouki O (2017) Neuroglobin protects astroglial cells from hydrogen peroxide-induced oxidative stress and apoptotic cell death. J Neurochem 140(1):151–169. https://doi.org/10.1111/jnc.13876

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Chen YX, Zeng ZC, Sun J, Zeng HY, Huang Y, Zhang ZY (2015) Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells. J Radiat Res 56(4):700–708. https://doi.org/10.1093/jrr/rrv026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Yu Z, Poppe JL, Wang X (2013) Mitochondrial mechanisms of neuroglobin's neuroprotection. Oxidative Med Cell Longev 2013:756989. https://doi.org/10.1155/2013/756989

    CAS  Article  Google Scholar 

  26. 26.

    Lan WB, Lin JH, Chen XW, Wu CY, Zhong GX, Zhang LQ, Lin WP, Liu WN et al (2014) Overexpressing neuroglobin improves functional recovery by inhibiting neuronal apoptosis after spinal cord injury. Brain Res 1562:100–108. https://doi.org/10.1016/j.brainres.2014.03.020

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Lechauve C, Augustin S, Roussel D, Sahel JA, Corral-Debrinski M (2013) Neuroglobin involvement in visual pathways through the optic nerve. Biochim Biophys Acta 1834(9):1772–1778. https://doi.org/10.1016/j.bbapap.2013.04.014

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Avivi A, Gerlach F, Joel A, Reuss S, Burmester T, Nevo E, Hankeln T (2010) Neuroglobin, cytoglobin, and myoglobin contribute to hypoxia adaptation of the subterranean mole rat Spalax. Proc Natl Acad Sci U S A 107(50):21570–21575. https://doi.org/10.1073/pnas.1015379107

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Zhao S, Yu Z, Zhao G, Xing C, Hayakawa K, Whalen MJ, Lok JM, Lo EH et al (2012) Neuroglobin-overexpression reduces traumatic brain lesion size in mice. BMC Neurosci 13:67. https://doi.org/10.1186/1471-2202-13-67

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Yu Z, Liu N, Liu J, Yang K, Wang X (2012) Neuroglobin, a novel target for endogenous neuroprotection against stroke and neurodegenerative disorders. Int J Mol Sci 13(6):6995–7014. https://doi.org/10.3390/ijms13066995

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Taylor JM, Kelley B, Gregory EJ, Berman NE (2014) Neuroglobin overexpression improves sensorimotor outcomes in a mouse model of traumatic brain injury. Neurosci Lett 577:125–129. https://doi.org/10.1016/j.neulet.2014.03.012

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Zhou Z, Chen Y, Zhang H, Min S, Yu B, He B, Jin A (2013) Comparison of mesenchymal stromal cells from human bone marrow and adipose tissue for the treatment of spinal cord injury. Cytotherapy 15(4):434–448. https://doi.org/10.1016/j.jcyt.2012.11.015

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Avila-Rodriguez M, Garcia-Segura LM, Hidalgo-Lanussa O, Baez E, Gonzalez J, Barreto GE (2016) Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression. Mol Cell Endocrinol 433:35–46. https://doi.org/10.1016/j.mce.2016.05.024

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Sasaki S, Futagi Y, Kobayashi M, Ogura J, Iseki K (2015) Functional characterization of 5-oxoproline transport via SLC16A1/MCT1. J Biol Chem 290(4):2303–2311. https://doi.org/10.1074/jbc.M114.581892

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Cabezas R, Avila MF, Gonzalez J, El-Bacha RS, Barreto GE (2015) PDGF-BB protects mitochondria from rotenone in T98G cells. Neurotox Res 27(4):355–367. https://doi.org/10.1007/s12640-014-9509-5

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Mimura J, Kosaka K, Maruyama A, Satoh T, Harada N, Yoshida H, Satoh K, Yamamoto M et al (2011) Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes. J Biochem 150(2):209–217. https://doi.org/10.1093/jb/mvr065

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Bourguignon LY, Gilad E, Peyrollier K, Brightman A, Swanson RA (2007) Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes. J Neurochem 101(4):1002–1017. https://doi.org/10.1111/j.1471-4159.2007.04485.x

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Ouyang YB, Xu LJ, Emery JF, Lee AS, Giffard RG (2011) Overexpressing GRP78 influences Ca2+ handling and function of mitochondria in astrocytes after ischemia-like stress. Mitochondrion 11(2):279–286. https://doi.org/10.1016/j.mito.2010.10.007

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Vomelova I, Vaníčková Z, Šedo A (2009) Technical note methods of RNA purification. All ways (should) lead to Rome. Folia Biologica (Praha) 55:243–251

    CAS  Google Scholar 

  40. 40.

    Scientific TF (2015) Real-time PCR Solutions.

  41. 41.

    Taylor SC, Berkelman T, Yadav G, Hammond M (2013) A defined methodology for reliable quantification of Western blot data. Mol Biotechnol 55(3):217–226. https://doi.org/10.1007/s12033-013-9672-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Gassmann M, Grenacher B, Rohde B, Vogel J (2009) Quantifying Western blots: pitfalls of densitometry. Electrophoresis 30(11):1845–1855. https://doi.org/10.1002/elps.200800720

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Voloboueva LA, Lee SW, Emery JF, Palmer TD, Giffard RG (2010) Mitochondrial protection attenuates inflammation-induced impairment of neurogenesis in vitro and in vivo. J Neurosci 30(37):12242–12251. https://doi.org/10.1523/JNEUROSCI.1752-10.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP et al (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28(16):4115–4122. https://doi.org/10.1523/JNEUROSCI.5308-07.2008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Wang H, Joseph JA (1999) Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27(5–6):612–616

    CAS  Article  Google Scholar 

  46. 46.

    Alarifi S, Ali D, Alkahtani S (2015) Nanoalumina induces apoptosis by impairing antioxidant enzyme systems in human hepatocarcinoma cells. Int J Nanomedicine 10:3751–3760. https://doi.org/10.2147/IJN.S82050

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Pokrzywinski KL, Tilney CL, Warner ME, Coyne KJ (2017) Cell cycle arrest and biochemical changes accompanying cell death in harmful dinoflagellates following exposure to bacterial algicide IRI-160AA. Sci Rep 7:45102. https://doi.org/10.1038/srep45102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Jeong SH, Kim HK, Song IS, Noh SJ, Marquez J, Ko KS, Rhee BD, Kim N et al (2014) Echinochrome a increases mitochondrial mass and function by modulating mitochondrial biogenesis regulatory genes. Marine Drugs 12(8):4602–4615. https://doi.org/10.3390/md12084602

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Oliva CR, Moellering DR, Gillespie GY, Griguer CE (2011) Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One 6(9):e24665. https://doi.org/10.1371/journal.pone.0024665

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Hidalgo-Lanussa O, Avila-Rodriguez M, Baez-Jurado E, Zamudio J, Echeverria V, Garcia-Segura LM, Barreto GE (2018) Tibolone reduces oxidative damage and inflammation in microglia stimulated with palmitic acid through mechanisms involving estrogen receptor beta. Mol Neurobiol 55(7):5462–5477. https://doi.org/10.1007/s12035-017-0777-y

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Li Q, Lau A, Morris TJ, Guo L, Fordyce CB, Stanley EF (2004) A syntaxin 1, Galpha(o), and N-type calcium channel complex at a presynaptic nerve terminal: analysis by quantitative immunocolocalization. J Neurosci 24(16):4070–4081. https://doi.org/10.1523/JNEUROSCI.0346-04.2004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129(2):154–169. https://doi.org/10.1111/j.1365-2567.2009.03225.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154(2):204–219. https://doi.org/10.1111/imm.12922

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Kokiko-Cochran ON, Godbout JP (2018) The inflammatory continuum of traumatic brain injury and Alzheimer's disease. Front Immunol 9:672. https://doi.org/10.3389/fimmu.2018.00672

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Chung WS, Allen NJ, Eroglu C (2015) Astrocytes control synapse formation, function, and elimination. Cold Spring Harb Perspect Biol 7(9):a020370. https://doi.org/10.1101/cshperspect.a020370

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Becerra-Calixto A, Cardona-Gomez GP (2017) The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy. Front Mol Neurosci 10:88. https://doi.org/10.3389/fnmol.2017.00088

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Kimelberg HK, Nedergaard M (2010) Functions of astrocytes and their potential as therapeutic targets. Neurotherapeutics 7(4):338–353. https://doi.org/10.1016/j.nurt.2010.07.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Cekanaviciute E, Buckwalter MS (2016) Astrocytes: integrative regulators of neuroinflammation in stroke and other neurological diseases. Neurotherapeutics 13(4):685–701. https://doi.org/10.1007/s13311-016-0477-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37(9):608–620. https://doi.org/10.1016/j.it.2016.06.006

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Le Thuc O, Blondeau N, Nahon JL, Rovere C (2015) The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects. Ann N Y Acad Sci 1351:127–140. https://doi.org/10.1111/nyas.12855

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, Zahoor H, Saeed D et al (2017) Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci 11:216. https://doi.org/10.3389/fncel.2017.00216

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Cunningham CJ, Redondo-Castro E, Allan SM (2018) The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism:271678X18776802. https://doi.org/10.1177/0271678X18776802

    Article  Google Scholar 

  63. 63.

    Valencia J, Blanco B, Yanez R, Vazquez M, Herrero Sanchez C, Fernandez-Garcia M, Rodriguez Serrano C, Pescador D et al (2016) Comparative analysis of the immunomodulatory capacities of human bone marrow- and adipose tissue-derived mesenchymal stromal cells from the same donor. Cytotherapy 18(10):1297–1311. https://doi.org/10.1016/j.jcyt.2016.07.006

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Gimeno ML, Fuertes F, Barcala Tabarrozzi AE, Attorressi AI, Cucchiani R, Corrales L, Oliveira TC, Sogayar MC et al (2017) Pluripotent nontumorigenic adipose tissue-derived muse cells have immunomodulatory capacity mediated by transforming growth factor-beta1. Stem Cells Transl Med 6(1):161–173. https://doi.org/10.5966/sctm.2016-0014

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL et al (2016) Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 7:e2062. https://doi.org/10.1038/cddis.2015.327

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Hariri RJ, Chang VA, Barie PS, Wang RS, Sharif SF, Ghajar JB (1994) Traumatic injury induces interleukin-6 production by human astrocytes. Brain Res 636(1):139–142

    CAS  Article  Google Scholar 

  67. 67.

    Liu C, Cui G, Zhu M, Kang X, Guo H (2014) Neuroinflammation in Alzheimer's disease: chemokines produced by astrocytes and chemokine receptors. Int J Clin Exp Pathol 7(12):8342–8355

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Phuagkhaopong S, Ospondpant D, Kasemsuk T, Sibmooh N, Soodvilai S, Power C, Vivithanaporn P (2017) Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-kappaB pathways. Neurotoxicology 60:82–91. https://doi.org/10.1016/j.neuro.2017.03.001

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Gijbels K, Van Damme J, Proost P, Put W, Carton H, Billiau A (1990) Interleukin 6 production in the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol 20(1):233–235. https://doi.org/10.1002/eji.1830200134

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Jiang Y, Deacon R, Anthony DC, Campbell SJ (2008) Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases. Neurobiol Dis 32(1):125–132. https://doi.org/10.1016/j.nbd.2008.06.017

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240. https://doi.org/10.1038/sj.bjp.0706400

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Tehranian R, Andell-Jonsson S, Beni SM, Yatsiv I, Shohami E, Bartfai T, Lundkvist J, Iverfeldt K (2002) Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist. J Neurotrauma 19(8):939–951. https://doi.org/10.1089/089771502320317096

    Article  PubMed  Google Scholar 

  73. 73.

    Guida E, Stewart A (1998) Influence of hypoxia and glucose deprivation on tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor expression in human cultured monocytes. Cell Physiol Biochem 8(1–2):75–88. https://doi.org/10.1159/000016272

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Opal SM, DePalo VA (2000) Anti-inflammatory cytokines. Chest 117(4):1162–1172

    CAS  Article  Google Scholar 

  75. 75.

    Xia W, Peng GY, Sheng JT, Zhu FF, Guo JF, Chen WQ (2015) Neuroprotective effect of interleukin-6 regulation of voltage-gated Na(+) channels of cortical neurons is time- and dose-dependent. Neural Regen Res 10(4):610–617. https://doi.org/10.4103/1673-5374.155436

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8(9):1254–1266. https://doi.org/10.7150/ijbs.4679

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Jiang T, Cadenas E (2014) Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell 13(6):1059–1067. https://doi.org/10.1111/acel.12268

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Chen XL, Wang Y, Peng WW, Zheng YJ, Zhang TN, Wang PJ, Huang JD, Zeng QY (2018) Effects of interleukin-6 and IL-6/AMPK signaling pathway on mitochondrial biogenesis and astrocytes viability under experimental septic condition. Int Immunopharmacol 59:287–294. https://doi.org/10.1016/j.intimp.2018.04.020

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Jiang CL, Lu CL (1998) Interleukin-2 and its effects in the central nervous system. Biol Signals Recept 7(3):148–156. https://doi.org/10.1159/000014541

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Xie L, Choudhury GR, Winters A, Yang SH, Jin K (2015) Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol 45(1):180–191. https://doi.org/10.1002/eji.201444823

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Bhela S, Varanasi SK, Jaggi U, Sloan SS, Rajasagi NK, Rouse BT (2017) The plasticity and stability of regulatory T cells during viral-induced inflammatory lesions. J Immunol 199(4):1342–1352. https://doi.org/10.4049/jimmunol.1700520

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Rothhammer V, Quintana FJ (2015) Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol 37(6):625–638. https://doi.org/10.1007/s00281-015-0515-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Bajetto A, Bonavia R, Barbero S, Schettini G (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J Neurochem 82(6):1311–1329

    CAS  Article  Google Scholar 

  84. 84.

    Hao P, Liang Z, Piao H, Ji X, Wang Y, Liu Y, Liu R, Liu J (2014) Conditioned medium of human adipose-derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP-43 expression. Metab Brain Dis 29(1):193–205. https://doi.org/10.1007/s11011-014-9490-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Bruno V, Copani A, Besong G, Scoto G, Nicoletti F (2000) Neuroprotective activity of chemokines against N-methyl-D-aspartate or beta-amyloid-induced toxicity in culture. Eur J Pharmacol 399(2–3):117–121

    CAS  Article  Google Scholar 

  86. 86.

    Mamik MK, Ghorpade A (2016) CXCL8 as a potential therapeutic target for HIV-associated neurocognitive disorders. Curr Drug Targets 17(1):111–121

    CAS  Article  Google Scholar 

  87. 87.

    Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N (2008) CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med 205(11):2643–2655. https://doi.org/10.1084/jem.20080730

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Chaudhry H, Zhou J, Zhong Y, Ali MM, McGuire F, Nagarkatti PS, Nagarkatti M (2013) Role of cytokines as a double-edged sword in sepsis. In Vivo 27(6):669–684

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Linero I, Chaparro O (2014) Paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration. PLoS One 9(9):e107001. https://doi.org/10.1371/journal.pone.0107001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kilroy GE, Foster SJ, Wu X, Ruiz J, Sherwood S, Heifetz A, Ludlow JW, Stricker DM et al (2007) Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol 212(3):702–709. https://doi.org/10.1002/jcp.21068

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Wei X, Du Z, Zhao L, Feng D, Wei G, He Y, Tan J, Lee WH et al (2009) IFATS collection: the conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells 27(2):478–488. https://doi.org/10.1634/stemcells.2008-0333

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Kupcova Skalnikova H (2013) Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie 95(12):2196–2211. https://doi.org/10.1016/j.biochi.2013.07.015

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Deng LX, Hu J, Liu N, Wang X, Smith GM, Wen X, Xu XM (2011) GDNF modifies reactive astrogliosis allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury. Exp Neurol 229(2):238–250. https://doi.org/10.1016/j.expneurol.2011.02.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Cirillo G, Bianco MR, Colangelo AM, Cavaliere C, Daniele de L, Zaccaro L, Alberghina L, Papa M (2011) Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor. Neurobiol Dis 41(3):630–639. https://doi.org/10.1016/j.nbd.2010.11.012

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Dimitrov DH, Lee S, Yantis J, Honaker C, Braida N (2014) Cytokine serum levels as potential biological markers for the psychopathology in schizophrenia. Adv Psychiatry 2014:1–7

    Article  Google Scholar 

  96. 96.

    Holliday J, Gruol DL (1993) Cytokine stimulation increases intracellular calcium and alters the response to quisqualate in cultured cortical astrocytes. Brain Res 621(2):233–241

    CAS  Article  Google Scholar 

  97. 97.

    Galic MA, Riazi K, Pittman QJ (2012) Cytokines and brain excitability. Front Neuroendocrinol 33(1):116–125. https://doi.org/10.1016/j.yfrne.2011.12.002

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Shinotsuka T, Yasui M, Nuriya M (2014) Astrocytic gap junctional networks suppress cellular damage in an in vitro model of ischemia. Biochem Biophys Res Commun 444(2):171–176. https://doi.org/10.1016/j.bbrc.2014.01.035

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Helleringer R, Chever O, Daniel H, Galante M (2017) Oxygen and glucose deprivation induces Bergmann glia membrane depolarization and ca(2+) rises mainly mediated by K(+) and ATP increases in the extracellular space. Front Cell Neurosci 11:349. https://doi.org/10.3389/fncel.2017.00349

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Reuss B, von Bohlen und Halback O (2003) Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 313(2):139–157. https://doi.org/10.1007/s00441-003-0756-7

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N (2009) Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res 3(1):63–70. https://doi.org/10.1016/j.scr.2009.02.006

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Papazian I, Kyrargyri V, Evangelidou M, Voulgari-Kokota A, Probert L (2018) Mesenchymal stem cell protection of neurons against glutamate excitotoxicity involves reduction of NMDA-triggered calcium responses and surface GluR1, and is partly mediated by TNF. Int J Mol Sci 19 (3). https://doi.org/10.3390/ijms19030651

    Article  Google Scholar 

  103. 103.

    Taoufik E, Valable S, Muller GJ, Roberts ML, Divoux D, Tinel A, Voulgari-Kokota A, Tseveleki V et al (2007) FLIP(L) protects neurons against in vivo ischemia and in vitro glucose deprivation-induced cell death. J Neurosci 27(25):6633–6646. https://doi.org/10.1523/JNEUROSCI.1091-07.2007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Marchetti L, Klein M, Schlett K, Pfizenmaier K, Eisel UL (2004) Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J Biol Chem 279(31):32869–32881. https://doi.org/10.1074/jbc.M311766200

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Probert L (2015) TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302:2–22. https://doi.org/10.1016/j.neuroscience.2015.06.038

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Morales AP, Carvalho AC, Monteforte PT, Hirata H, Han SW, Hsu YT, Smaili SS (2011) Endoplasmic reticulum calcium release engages Bax translocation in cortical astrocytes. Neurochem Res 36(5):829–838. https://doi.org/10.1007/s11064-011-0411-8

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Verkhratsky A, Rodriguez JJ, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353(1–2):45–56. https://doi.org/10.1016/j.mce.2011.08.039

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Johnson GG, White MC, Wu JH, Vallejo M, Grimaldi M (2014) The deadly connection between endoplasmic reticulum, Ca2+, protein synthesis, and the endoplasmic reticulum stress response in malignant glioma cells. Neuro-Oncology 16(8):1086–1099. https://doi.org/10.1093/neuonc/nou012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Begum G, Kintner D, Liu Y, Cramer SW, Sun D (2012) DHA inhibits ER Ca2+ release and ER stress in astrocytes following in vitro ischemia. J Neurochem 120(4):622–630. https://doi.org/10.1111/j.1471-4159.2011.07606.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82(3):415–424

    CAS  Article  Google Scholar 

  111. 111.

    Reyes RC, Parpura V (2008) Mitochondria modulate Ca2+−dependent glutamate release from rat cortical astrocytes. J Neurosci 28(39):9682–9691. https://doi.org/10.1523/JNEUROSCI.3484-08.2008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Parpura V, Grubisic V, Verkhratsky A (2011) Ca(2+) sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta 1813(5):984–991. https://doi.org/10.1016/j.bbamcr.2010.11.006

    CAS  Article  PubMed  Google Scholar 

  113. 113.

    Voulgari-Kokota A, Fairless R, Karamita M, Kyrargyri V, Tseveleki V, Evangelidou M, Delorme B, Charbord P et al (2012) Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function. Exp Neurol 236(1):161–170. https://doi.org/10.1016/j.expneurol.2012.04.011

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Cheng B, Furukawa K, O'Keefe JA, Goodman Y, Kihiko M, Fabian T, Mattson MP (1995) Basic fibroblast growth factor selectively increases AMPA-receptor subunit GluR1 protein level and differentially modulates Ca2+ responses to AMPA and NMDA in hippocampal neurons. J Neurochem 65(6):2525–2536

    CAS  Article  Google Scholar 

  115. 115.

    Ranieri M, Brajkovic S, Riboldi G, Ronchi D, Rizzo F, Bresolin N, Corti S, Comi GP (2013) Mitochondrial fusion proteins and human diseases. Neurol Res Int 2013:293893. https://doi.org/10.1155/2013/293893

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Burte F, Carelli V, Chinnery PF, Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11(1):11–24. https://doi.org/10.1038/nrneurol.2014.228

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Qi X, Disatnik MH, Shen N, Sobel RA, Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell 22(2):256–265. https://doi.org/10.1091/mbc.E10-06-0551

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT (2004) Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci 117(Pt 7):1201–1210. https://doi.org/10.1242/jcs.01058

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Elgass K, Pakay J, Ryan MT, Palmer CS (2013) Recent advances into the understanding of mitochondrial fission. Biochim Biophys Acta 1833(1):150–161. https://doi.org/10.1016/j.bbamcr.2012.05.002

    CAS  Article  PubMed  Google Scholar 

  120. 120.

    Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S, Wieckowski MR, Rizzuto R (2006) Mitochondrial dynamics and Ca2+ signaling. Biochim Biophys Acta 1763(5–6):442–449. https://doi.org/10.1016/j.bbamcr.2006.04.002

    CAS  Article  PubMed  Google Scholar 

  121. 121.

    Bravo-Sagua R, Parra V, Lopez-Crisosto C, Diaz P, Quest AF, Lavandero S (2017) Calcium transport and signaling in mitochondria. Comp Physiol 7(2):623–634. https://doi.org/10.1002/cphy.c160013

    Article  Google Scholar 

  122. 122.

    Ogunbileje JO, Porter C, Herndon DN, Chao T, Abdelrahman DR, Papadimitriou A, Chondronikola M, Zimmers TA et al (2016) Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma. Am J Phys Endocrinol Metab 311(2):E436–E448. https://doi.org/10.1152/ajpendo.00535.2015

    Article  Google Scholar 

  123. 123.

    Eisner V, Picard M, Hajnóczky G (2018) Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol 1

  124. 124.

    Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28(11):1589–1600. https://doi.org/10.1038/emboj.2009.89

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Jagasia R, Grote P, Westermann B, Conradt B (2005) DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433(7027):754–760. https://doi.org/10.1038/nature03316

    CAS  Article  PubMed  Google Scholar 

  126. 126.

    Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM, Hill RB, Basanez G et al (2004) Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev 18(22):2785–2797. https://doi.org/10.1101/gad.1247904

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34–39. https://doi.org/10.1111/j.1749-6632.2010.05629.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Alavi MV, Fuhrmann N (2013) Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics. Mol Neurodegener 8:32. https://doi.org/10.1186/1750-1326-8-32

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Mishra P, Chan DC (2016) Metabolic regulation of mitochondrial dynamics. J Cell Biol 212(4):379–387. https://doi.org/10.1083/jcb.201511036

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598. https://doi.org/10.1038/ncb2220

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15(11):5001–5011. https://doi.org/10.1091/mbc.e04-04-0294

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Cereghetti GM, Costa V, Scorrano L (2010) Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin. Cell Death Differ 17(11):1785–1794. https://doi.org/10.1038/cdd.2010.61

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1(4):515–525

    CAS  Article  Google Scholar 

  134. 134.

    Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126(1):177–189. https://doi.org/10.1016/j.cell.2006.06.025

    CAS  Article  Google Scholar 

  135. 135.

    Elachouri G, Vidoni S, Zanna C, Pattyn A, Boukhaddaoui H, Gaget K, Yu-Wai-Man P, Gasparre G et al (2011) OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res 21(1):12–20. https://doi.org/10.1101/gr.108696.110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278(10):7743–7746. https://doi.org/10.1074/jbc.C200677200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Mizushima N (2005) The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ 12(Suppl 2):1535–1541. https://doi.org/10.1038/sj.cdd.4401728

    CAS  Article  PubMed  Google Scholar 

  138. 138.

    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721

    CAS  Article  Google Scholar 

  139. 139.

    Wu YT, Tan HL, Huang Q, Kim YS, Pan N, Ong WY, Liu ZG, Ong CN et al (2008) Autophagy plays a protective role during zVAD-induced necrotic cell death. Autophagy 4(4):457–466

    CAS  Article  Google Scholar 

  140. 140.

    Cecconi F, Levine B (2008) The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell 15(3):344–357. https://doi.org/10.1016/j.devcel.2008.08.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141.

    White KE, Davies VJ, Hogan VE, Piechota MJ, Nichols PP, Turnbull DM, Votruba M (2009) OPA1 deficiency associated with increased autophagy in retinal ganglion cells in a murine model of dominant optic atrophy. Invest Ophthalmol Vis Sci 50(6):2567–2571. https://doi.org/10.1167/iovs.08-2913

    Article  PubMed  Google Scholar 

  142. 142.

    Kane MS, Alban J, Desquiret-Dumas V, Gueguen N, Ishak L, Ferre M, Amati-Bonneau P, Procaccio V et al (2017) Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. J Cell Mol Med 21(10):2284–2297. https://doi.org/10.1111/jcmm.13149

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Gomes LC, Scorrano L (2011) Mitochondrial elongation during autophagy: a stereotypical response to survive in difficult times. Autophagy 7(10):1251–1253. https://doi.org/10.4161/auto.7.10.16771

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Gomes LC, Scorrano L (2013) Mitochondrial morphology in mitophagy and macroautophagy. Biochim Biophys Acta 1833(1):205–212. https://doi.org/10.1016/j.bbamcr.2012.02.012

    CAS  Article  PubMed  Google Scholar 

  145. 145.

    Hackenbrock CR (1968) Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci U S A 61(2):598–605

    CAS  Article  Google Scholar 

  146. 146.

    Pidoux G, Witczak O, Jarnaess E, Myrvold L, Urlaub H, Stokka AJ, Kuntziger T, Tasken K (2011) Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis. EMBO J 30(21):4371–4386. https://doi.org/10.1038/emboj.2011.365

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Seo BB, Nakamaru-Ogiso E, Flotte TR, Matsuno-Yagi A, Yagi T (2006) In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease. J Biol Chem 281(20):14250–14255. https://doi.org/10.1074/jbc.M600922200

    CAS  Article  PubMed  Google Scholar 

  148. 148.

    Marella M, Seo BB, Yagi T, Matsuno-Yagi A (2009) Parkinson's disease and mitochondrial complex I: a perspective on the Ndi1 therapy. J Bioenerg Biomembr 41(6):493–497. https://doi.org/10.1007/s10863-009-9249-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Seo BB, Nakamaru-Ogiso E, Cruz P, Flotte TR, Yagi T, Matsuno-Yagi A (2004) Functional expression of the single subunit NADH dehydrogenase in mitochondria in vivo: a potential therapy for complex I deficiencies. Hum Gene Ther 15(9):887–895. https://doi.org/10.1089/hum.2004.15.887

    CAS  Article  PubMed  Google Scholar 

  150. 150.

    Yu Z, Zhang Y, Liu N, Yuan J, Lin L, Zhuge Q, Xiao J, Wang X (2016) Roles of neuroglobin binding to mitochondrial complex III subunit cytochrome c1 in oxygen-glucose deprivation-induced neurotoxicity in primary neurons. Mol Neurobiol 53(5):3249–3257. https://doi.org/10.1007/s12035-015-9273-4

    CAS  Article  PubMed  Google Scholar 

  151. 151.

    Ma WW, Hou CC, Zhou X, Yu HL, Xi YD, Ding J, Zhao X, Xiao R (2013) Genistein alleviates the mitochondria-targeted DNA damage induced by beta-amyloid peptides 25-35 in C6 glioma cells. Neurochem Res 38(7):1315–1323. https://doi.org/10.1007/s11064-013-1019-y

    CAS  Article  PubMed  Google Scholar 

  152. 152.

    Hawkins PT, Anderson KE, Davidson K, Stephens LR (2006) Signalling through class I PI3Ks in mammalian cells. Biochem Soc Trans 34(Pt 5):647–662. https://doi.org/10.1042/BST0340647

    CAS  Article  PubMed  Google Scholar 

  153. 153.

    Anderson CN, Tolkovsky AM (1999) A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci 19(2):664–673

    CAS  Article  Google Scholar 

  154. 154.

    de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM (2015) Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem Biol Interact 242:396–406. https://doi.org/10.1016/j.cbi.2015.11.003

    CAS  Article  PubMed  Google Scholar 

  155. 155.

    Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI (2011) Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell 8(1):59–71. https://doi.org/10.1016/j.stem.2010.11.028

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Zhang Q, Liu G, Wu Y, Sha H, Zhang P, Jia J (2011) BDNF promotes EGF-induced proliferation and migration of human fetal neural stem/progenitor cells via the PI3K/Akt pathway. Molecules 16(12):10146–10156. https://doi.org/10.3390/molecules161210146

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Zhao J, Cheng YY, Fan W, Yang CB, Ye SF, Cui W, Wei W, Lao LX et al (2015) Botanical drug puerarin coordinates with nerve growth factor in the regulation of neuronal survival and neuritogenesis via activating ERK1/2 and PI3K/Akt signaling pathways in the neurite extension process. CNS Neurosci Ther 21(1):61–70. https://doi.org/10.1111/cns.12334

    CAS  Article  PubMed  Google Scholar 

  158. 158.

    Nguyen TL, Kim CK, Cho JH, Lee KH, Ahn JY (2010) Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7/IGF-IR [corrected]. Exp Mol Med 42(8):583–595. https://doi.org/10.3858/emm.2010.42.8.060

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Lotfinia M, Kadivar M, Piryaei A, Pournasr B, Sardari S, Sodeifi N, Sayahpour FA, Baharvand H (2016) Effect of secreted molecules of human embryonic stem cell-derived mesenchymal stem cells on acute hepatic failure model. Stem Cells Dev 25(24):1898–1908. https://doi.org/10.1089/scd.2016.0244

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Zagoura DS, Roubelakis MG, Bitsika V, Trohatou O, Pappa KI, Kapelouzou A, Antsaklis A, Anagnou NP (2012) Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure. Gut 61(6):894–906. https://doi.org/10.1136/gutjnl-2011-300908

    CAS  Article  PubMed  Google Scholar 

  161. 161.

    Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105(1):93–98

    Article  Google Scholar 

  162. 162.

    Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, Surh YJ (2008) (−)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch Biochem Biophys 476(2):171–177. https://doi.org/10.1016/j.abb.2008.04.003

    CAS  Article  PubMed  Google Scholar 

  163. 163.

    Liu J, Yu Z, Guo S, Lee SR, Xing C, Zhang C, Gao Y, Nicholls DG et al (2009) Effects of neuroglobin overexpression on mitochondrial function and oxidative stress following hypoxia/reoxygenation in cultured neurons. J Neurosci Res 87(1):164–170. https://doi.org/10.1002/jnr.21826

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Duong TT, Witting PK, Antao ST, Parry SN, Kennerson M, Lai B, Vogt S, Lay PA et al (2009) Multiple protective activities of neuroglobin in cultured neuronal cells exposed to hypoxia re-oxygenation injury. J Neurochem 108(5):1143–1154. https://doi.org/10.1111/j.1471-4159.2008.05846.x

    CAS  Article  PubMed  Google Scholar 

  165. 165.

    Yu Z, Xu J, Liu N, Wang Y, Li X, Pallast S, van Leyen K, Wang X (2012) Mitochondrial distribution of neuroglobin and its response to oxygen-glucose deprivation in primary-cultured mouse cortical neurons. Neuroscience 218:235–242. https://doi.org/10.1016/j.neuroscience.2012.05.054

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Fiocchetti M, Cipolletti M, Leone S, Naldini A, Carraro F, Giordano D, Verde C, Ascenzi P et al (2016) Neuroglobin in breast cancer cells: effect of hypoxia and oxidative stress on protein level, localization, and anti-apoptotic function. PLoS One 11(5):e0154959. https://doi.org/10.1371/journal.pone.0154959

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. 167.

    De Marinis E, Fiocchetti M, Acconcia F, Ascenzi P, Marino M (2013) Neuroglobin upregulation induced by 17beta-estradiol sequesters cytocrome c in the mitochondria preventing H2O2-induced apoptosis of neuroblastoma cells. Cell Death Dis 4:e508. https://doi.org/10.1038/cddis.2013.30

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Gorgun FM, Zhuo M, Singh S, Englander EW (2014) Neuroglobin mitigates mitochondrial impairments induced by acute inhalation of combustion smoke in the mouse brain. Inhal Toxicol 26(6):361–369. https://doi.org/10.3109/08958378.2014.902147

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Cabezas R, Vega-Vela NE, Gonzalez-Sanmiguel J, Gonzalez J, Esquinas P, Echeverria V, Barreto GE (2018) PDGF-BB preserves mitochondrial morphology, attenuates ROS production, and upregulates neuroglobin in an astrocytic model under rotenone insult. Mol Neurobiol 55(4):3085–3095. https://doi.org/10.1007/s12035-017-0567-6

    CAS  Article  PubMed  Google Scholar 

  170. 170.

    Jin K, Mao X, Xie L, Greenberg DA (2012) Interactions between vascular endothelial growth factor and neuroglobin. Neurosci Lett 519(1):47–50. https://doi.org/10.1016/j.neulet.2012.05.018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Zhu L, Huang L, Wen Q, Wang T, Qiao L, Jiang L (2017) Recombinant human erythropoietin offers neuroprotection through inducing endogenous erythropoietin receptor and neuroglobin in a neonatal rat model of periventricular white matter damage. Neurosci Lett 650:12–17. https://doi.org/10.1016/j.neulet.2017.03.024

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr. Jorge Andrés Afanador and the staff of the cosmetic surgery Clinic DHARA in Bogotá, Colombia, for the adipose tissue samples. This work was supported in part by grants PUJ IDs 6260 and 7115 to GEB and 6278 to JG and scholarship for doctoral studies awarded by the Vicerrectoría Académica of PUJ to EB.

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Correspondence to George E. Barreto.

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Baez-Jurado, E., Guio-Vega, G., Hidalgo-Lanussa, O. et al. Mitochondrial Neuroglobin Is Necessary for Protection Induced by Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells in Astrocytic Cells Subjected to Scratch and Metabolic Injury. Mol Neurobiol 56, 5167–5187 (2019). https://doi.org/10.1007/s12035-018-1442-9

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Keywords

  • Astrocytes
  • Scratch assay
  • Mesenchymal stem cells
  • Inflammation
  • Conditioned medium
  • Neuroglobin