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Oxygen Glucose Deprivation/Reperfusion Astrocytes Promotes Primary Neural Stem/Progenitor Cell Proliferation by Releasing High-Mobility Group Box 1

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Abstract

Cerebral ischemia/reperfusion is known to activate endogenous neural stem/progenitor cell (NS/PC) proliferation, but the mechanisms leading to NS/PC proliferation remain unknown. Astrocytes are vital components of the neurogenic niche and play a crucial role in regulating NS/PC proliferation and differentiation. After focal cerebral ischemia/reperfusion (I/R), astrocytes release a damage-associated molecular-pattern molecule called high-mobility group box 1 (HMGB1). Since HMGB1 is critical for NS/PC proliferation during brain development, we modeled I/R using glucose deprivation/reperfusion (OGD/R) in vitro and examined the effect of HMGB1 released by astrocytes on NS/PC proliferation. Further, we determined the role of the PI3K/Akt signaling pathway in this process. Using conditioned media from OGD/R astrocytes with or without RNA interference for HMGB1, as well as with anti-HMGB1 antibodies, we evaluated the effect of astrocyte-derived HMGB1 on NS/PC proliferation. Using the potent PI3K/Akt inhibitor, LY294002, we explored the likely mechanism of HMGB1-induced NS/PC proliferation. OGD/R astrocyte-conditioned media (ACM) increased NS/PC proliferation, and HMGB1 RNA interference prevented this effect. Using an HMGB1 neutralizing antibody in OGD/R ACM also abrogated NS/PC proliferation. LY294002 effectively reduced phospho-Akt levels and reduced NS/PC proliferation induced by HMGB1 in vitro. Our data demonstrate that HMGB1 released by OGD/R astrocytes promotes NS/PC proliferation through activation of the PI3K/Akt signaling pathway. Local HMGB1 release may induce endogenous NS/PC to proliferate following cerebral I/R and suggests that HMGB1 may play a pivotal role in brain tissue repair after an ischemic event.

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References

  1. Nakagomi T, Taguchi A, Fujimori Y, Saino O, Nakano-Doi A, Kubo S, Gotoh A, Soma T, Yoshikawa H, Nishizaki T, Nakagomi N, Stern DM, Matsuyama T (2009) Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice. Eur J Neurosci 29:1842–1852

    Article  PubMed  Google Scholar 

  2. Sims JR, Lee SW, Topalkara K, Qiu J, Xu J, Zhou Z, Moskowitz MA (2009) Sonic hedgehog regulates ischemia/hypoxia-induced neural progenitor proliferation. Stroke 40:3618–3626

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Cao X, Li LP, Qin XH, Li SJ, Zhang M, Wang Q, Hu HH, Fang YY, Gao YB, Li XW, Sun LR, Xiong WC, Gao TM, Zhu XH (2013) Astrocytic adenosine 5′-triphosphate release regulates the proliferation of neural stem cells in the adult hippocampus. Stem Cells 31:1633–1643

    Article  CAS  PubMed  Google Scholar 

  4. Go HS, Shin CY, Lee SH, Jeon SJ, Kim KC, Choi CS, Ko KH (2009) Increased proliferation and gliogenesis of cultured rat neural progenitor cells by lipopolysaccharide-stimulated astrocytes. NeuroImmunoModulation 16:365–376

    Article  CAS  PubMed  Google Scholar 

  5. Lee C, Hu J, Ralls S, Kitamura T, Loh YP, Yang Y, Mukouyama YS, Ahn S (2012) The molecular profiles of neural stem cell niche in the adult subventricular zone. PLoS One 7:e50501

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S, Heinrich C, Tiedt S, Colak D, Dichgans M, Fischer IR, Plesnila N, Staufenbiel M, Haass C, Snapyan M, Saghatelyan A, Tsai LH, Fischer A, Grobe K, Dimou L, Gotz M (2013) Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. [corrected]. Cell Stem Cell 12:426–439

    Article  CAS  PubMed  Google Scholar 

  7. Hayakawa K, Pham LD, Katusic ZS, Arai K, Lo EH (2012) Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc Natl Acad Sci USA 109:7505–7510

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Kim SW, Jin Y, Shin JH, Kim ID, Lee HK, Park S, Han PL, Lee JK (2012) Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion. Neurobiol Dis 46:147–156

    Article  CAS  PubMed  Google Scholar 

  9. Zhang J, Takahashi HK, Liu K, Wake H, Liu R, Maruo T, Date I, Yoshino T, Ohtsuka A, Mori S, Nishibori M (2011) Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke 42:1420–1428

    Article  CAS  PubMed  Google Scholar 

  10. Kim SW, Lim CM, Kim JB, Shin JH, Lee S, Lee M, Lee JK (2011) Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway. Neurotox Res 20:159–169

    Article  CAS  PubMed  Google Scholar 

  11. Guazzi S, Strangio A, Franzi AT, Bianchi ME (2003) HMGB1, an architectural chromatin protein and extracellular signalling factor, has a spatially and temporally restricted expression pattern in mouse brain. Gene Expr Patterns 3:29–33

    Article  CAS  PubMed  Google Scholar 

  12. Meneghini V, Bortolotto V, Francese MT, Dellarole A, Carraro L, Terzieva S, Grilli M (2013) High-mobility group box-1 protein and beta-amyloid oligomers promote neuronal differentiation of adult hippocampal neural progenitors via receptor for advanced glycation end products/nuclear factor-kappaB axis: relevance for Alzheimer’s disease. J Neurosci 33:6047–6059

    Article  CAS  PubMed  Google Scholar 

  13. Zhao X, Kuja-Panula J, Rouhiainen A, Chen YC, Panula P, Rauvala H (2011) High mobility group box-1 (HMGB1; amphoterin) is required for zebrafish brain development. J Biol Chem 286:23200–23213

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Guo J, Duckles SP, Weiss JH, Li X, Krause DN (2012) 17beta-Estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen-glucose deprivation/reperfusion. Free Radic Biol Med 52:2151–2160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Louis SA, Mak CK, Reynolds BA (2013) Methods to culture, differentiate, and characterize neural stem cells from the adult and embryonic mouse central nervous system. Methods Mol Biol 946:479–506

    Article  CAS  PubMed  Google Scholar 

  16. Meneghini V, Francese MT, Carraro L, Grilli M (2010) A novel role for the receptor for advanced glycation end-products in neural progenitor cells derived from adult subventricular zone. Mol Cell Neurosci 45:139–150

    Article  CAS  PubMed  Google Scholar 

  17. Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–6421

    Article  CAS  PubMed  Google Scholar 

  18. Chen X, Tian Y, Yao L, Zhang J, Liu Y (2010) Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. Neuroscience 165:705–714

    Article  CAS  PubMed  Google Scholar 

  19. Yang C, Rahimpour S, Yu AC, Lonser RR, Zhuang Z (2013) Regulation and dysregulation of astrocyte activation and implications in tumor formation. Cell Mol Life Sci 70:4201–4211

    Article  CAS  PubMed  Google Scholar 

  20. Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434

    Article  PubMed  Google Scholar 

  21. Bao Y, Qin L, Kim E, Bhosle S, Guo H, Febbraio M, Haskew-Layton RE, Ratan R, Cho S (2012) CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab 32:1567–1577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Jeong SR, Kwon MJ, Lee HG, Joe EH, Lee JH, Kim SS, Suh-Kim H, Kim BG (2012) Hepatocyte growth factor reduces astrocytic scar formation and promotes axonal growth beyond glial scars after spinal cord injury. Exp Neurol 233:312–322

    Article  CAS  PubMed  Google Scholar 

  23. Kawano H, Kimura-Kuroda J, Komuta Y, Yoshioka N, Li HP, Kawamura K, Li Y, Raisman G (2012) Role of the lesion scar in the response to damage and repair of the central nervous system. Cell Tissue Res 349:169–180

    Article  PubMed Central  PubMed  Google Scholar 

  24. Brambilla R, Morton PD, Ashbaugh JJ, Karmally S, Lambertsen KL, Bethea JR (2014) Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia 62:452–467

    Article  PubMed  Google Scholar 

  25. Lau LT, Yu AC (2001) Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 18:351–359

    Article  CAS  PubMed  Google Scholar 

  26. Hayakawa K, Arai K, Lo EH (2010) Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. Glia 58:1007–1015

    PubMed  Google Scholar 

  27. Liu K, Mori S, Takahashi HK, Tomono Y, Wake H, Kanke T, Sato Y, Hiraga N, Adachi N, Yoshino T, Nishibori M (2007) Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J 21:3904–3916

    Article  CAS  PubMed  Google Scholar 

  28. Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi P (2002) HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine 18:231–236

    Article  CAS  PubMed  Google Scholar 

  29. Liu H, Yao YM, Ding LH, Zhang H, Yuan B, Song Q, Ye QN, Huang CF, Sheng ZY (2009) High mobility group box-1 protein acts as a coactivator of nuclear factor of activated T cells-2 in promoting interleukin-2 transcription. Int J Biochem Cell Biol 41:641–648

    Article  CAS  PubMed  Google Scholar 

  30. Kim JB, Lim CM, Yu YM, Lee JK (2008) Induction and subcellular localization of high-mobility group box-1 (HMGB1) in the postischemic rat brain. J Neurosci Res 86:1125–1131

    Article  CAS  PubMed  Google Scholar 

  31. Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938

    Article  CAS  PubMed  Google Scholar 

  32. Muhammad S, Barakat W, Stoyanov S, Murikinati S, Yang H, Tracey KJ, Bendszus M, Rossetti G, Nawroth PP, Bierhaus A, Schwaninger M (2008) The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci 28:12023–12031

    Article  CAS  PubMed  Google Scholar 

  33. Hayakawa K, Nakano T, Irie K, Higuchi S, Fujioka M, Orito K, Iwasaki K, Jin G, Lo EH, Mishima K, Fujiwara M (2010) Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab 30:871–882

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Lei C, Lin S, Zhang C, Tao W, Dong W, Hao Z, Liu M, Wu B (2013) Effects of high-mobility group box1 on cerebral angiogenesis and neurogenesis after intracerebral hemorrhage. Neuroscience 229:12–19

    Article  CAS  PubMed  Google Scholar 

  35. Gabryel B, Bielecka A, Bernacki J, Labuzek K, Herman ZS (2011) Immunosuppressant cytoprotection correlates with HMGB1 suppression in primary astrocyte cultures exposed to combined oxygen-glucose deprivation. Pharmacol Rep 63:392–402

    Article  CAS  PubMed  Google Scholar 

  36. Yoshida H, Mimura J, Imaizumi T, Matsumiya T, Ishikawa A, Metoki N, Tanji K, Ota K, Hayakari R, Kosaka K, Itoh K, Satoh K (2011) Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation. Neurosci Res 69:291–298

    Article  CAS  PubMed  Google Scholar 

  37. Koyama Y, Maebara Y, Hayashi M, Nagae R, Tokuyama S, Michinaga S (2012) Endothelins reciprocally regulate VEGF-A and angiopoietin-1 production in cultured rat astrocytes: implications on astrocytic proliferation. Glia 60:1954–1963

    Article  PubMed  Google Scholar 

  38. Kuric E, Wieloch T, Ruscher K (2013) Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke. Exp Neurol 247:202–208

    Article  CAS  PubMed  Google Scholar 

  39. Modi KK, Sendtner M, Pahan K (2013) Up-regulation of Ciliary Neurotrophic Factor in Astrocytes by Aspirin: implications for remyelination in multiple sclerosis. J Biol Chem 288:18533–18545

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Sung SM, Jung DS, Kwon CH, Park JY, Kang SK, Kim YK (2007) Hypoxia/reoxygenation stimulates proliferation through PKC-dependent activation of ERK and Akt in mouse neural progenitor cells. Neurochem Res 32:1932–1939

    Article  CAS  PubMed  Google Scholar 

  41. Kim JH, Nam SW, Kim BW, Choi W, Lee JH, Kim WJ, Choi YH (2010) Astaxanthin Improves Stem Cell Potency via an Increase in the Proliferation of Neural Progenitor Cells. Int J Mol Sci 11:5109–5119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Yang J, Chen L, Ding J, Rong H, Dong W, Li X (2012) High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation. Mol Biol Rep 39:3361–3367

    Article  CAS  PubMed  Google Scholar 

  43. Lao CL, Lu CS, Chen JC (2013) Dopamine D3 receptor activation promotes neural stem/progenitor cell proliferation through AKT and ERK1/2 pathways and expands type-B and -C cells in adult subventricular zone. Glia 61:475–489

    Article  PubMed  Google Scholar 

  44. 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 8:59–71

    Article  PubMed Central  PubMed  Google Scholar 

  45. 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 16:10146–10156

    Article  CAS  PubMed  Google Scholar 

  46. Peltier J, O’Neill A, Schaffer DV (2007) PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol 67:1348–1361

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by the National Natural Science Foundation of China (No. 30470606) and the Program of the Traditional Chinese Medical Research of Chongqing Municipal Health Bureau (No. 2003-B-16).

Conflict of interest

All authors declare that they have no perceived or actual conflict of interests.

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 40016, China

    Man Li, Chenchen Xie & Yong Luo

  2. Department of Neurology, The Second Hospital of Shanxi Medical University, 382 Wu Yi Road, Taiyuan, 030001, Shanxi, China

    Man Li

  3. Department of Orthopedics, Shanxi Academy of Medical Sciences, Shanxi Dayi Hospital, 99 Longcheng Street, Taiyuan, 030032, China

    Lin Sun

  4. Basic Medicine College of Shanxi Medical University, Taiyuan, 030001, China

    Yuan Li

  5. Chongqing Key Laboratory of Neurology, 1 Youyi Road, Yuzhong District, Chongqing, 40016, China

    Chenchen Xie & Yong Luo

  6. Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Dong Wan

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  1. Man Li
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Correspondence to Yong Luo.

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Li, M., Sun, L., Li, Y. et al. Oxygen Glucose Deprivation/Reperfusion Astrocytes Promotes Primary Neural Stem/Progenitor Cell Proliferation by Releasing High-Mobility Group Box 1. Neurochem Res 39, 1440–1450 (2014). https://doi.org/10.1007/s11064-014-1333-z

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  • DOI: https://doi.org/10.1007/s11064-014-1333-z

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