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Translational Stroke Research

, Volume 8, Issue 5, pp 449–460 | Cite as

Stroke Induces Mesenchymal Stem Cell Migration to Infarcted Brain Areas Via CXCR4 and C-Met Signaling

  • Oh Young BangEmail author
  • Gyeong Joon Moon
  • Dong Hee Kim
  • Ji Hyun Lee
  • Sooyoon Kim
  • Jeong Pyo Son
  • Yeon Hee Cho
  • Won Hyuk Chang
  • Yun-Hee Kim
  • the STARTING-2 trial investigators
Original Article

Abstract

Mesenchymal stem cells circulate between organs to repair and maintain tissues. Mesenchymal stem cells cultured with fetal bovine serum have therapeutic effects when intravenously administered after stroke. However, only a small number of mesenchymal stem cells reach the brain. We hypothesized that the serum from stroke patients increases mesenchymal stem cells trophism toward the infarcted brain area. Mesenchymal stem cells were grown in fetal bovine serum, normal serum from normal rats, or stroke serum from ischemic stroke rats. Compared to the fetal bovine serum group, the stroke serum group but not the normal serum group showed significantly greater migration toward the infarcted brain area in the in vitro and in vivo models (p < 0.05). Both C-X-C chemokine receptor type 4 and c-Met expression levels significantly increased in the stroke serum group than the others. The enhanced mesenchymal stem cells migration of the stroke serum group was abolished by inhibition of signaling. Serum levels of chemokines, cytokines, matrix metalloproteinase, and growth factors were higher in stroke serum than in normal serum. Behavioral tests showed a significant improvement in the recovery after stroke in the stroke serum group than the others. Stroke induces mesenchymal stem cells migration to the infarcted brain area via C-X-C chemokine receptor type 4 and c-Met signaling. Culture expansion using the serum from stroke patients could constitute a novel preconditioning method to enhance the therapeutic efficiency of mesenchymal stem cells.

Keywords

Stroke Mesenchymal stem cells Preconditioning Migration Homing Trophism 

Notes

Acknowledgements

This study was supported by a grant from the Korea Health Technology R&D Project, the Ministry of Health & Welfare (HI14C1624).

STem cell Application Researches and Trials In NeuroloGy (STARTING)-2 collaborators: Oh Young Bang, MD, PhD; Ji Hyun Lee; Gyeong Joon Moon, PhD; Yeon Hee Cho, MS; Ji Hee Sung; Soo Yoon Kim, MS; Jeong Pyo Son, MS; Dong Hee Kim, MS; Jong-Won Chung, MD; Mi Ji Lee, MD; Suk Jae Kim, MD; Soo Kyoung Kim, MD; Yoon Mi Kang, MS; Yong Man Kim, PhD; Hyun Soo Kim, MD, PhD; Jun Ho Jang, MD, PhD; Won Hyuk Chang, MD, PhD; Yun-Hee Kim, MD, PhD.

Author’s Contributions

O.Y.B.: conception and design, manuscript writing, financial support, collection and/or assembly of data, data analysis and interpretation, administrative support, final approval of manuscript; D.H.K.: provision of study material, collection and/or assembly of data, data analysis and interpretation; J.H.L.: collection and/or assembly of data, data analysis and interpretation, provision of study material; S.Y.K.: collection and/or assembly of data, data analysis and interpretation, provision of study material; J.P.S.: collection and/or assembly of data, data analysis and interpretation, provision of study material; Y.H.C.: collection and/or assembly of data, data analysis and interpretation, provision of study material; J.M.C.: collection and/or assembly of data, provision of study material; W.H.C.: provision of study material or patients, administrative support; Y.H.K.: provision of study material or patients, administrative support; G.J.M: conception and design, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflicts of interest to report.

Funding

This study was supported by a grant from the Korea Health Technology R&D Project, the Ministry of Health & Welfare (HI14C1624).

Ethical Approval

In this study, all human subject research was approved by the local institutional review board (Samsung Medical Center Institutional Review Board, Approval No. SMC 2011-10-047-047). All patients or guardians of patients provided written informed consent to participate in this study. All animal experiments were approved by Institutional Animal Care and Use Committee (IACUC) of Samsung Biomedical Research Institute (SBRI, Approval No. 201300117002) and performed under the Institute of Laboratory Animal Resources (ILAR) guidelines. All animals were maintained in compliance with the relevant laws and institutional guidelines of Laboratory Animal Research Center (LARC; AAALAC International approved facility, No. 001003) at the Samsung Medical Center.

Supplementary material

12975_2017_538_MOESM1_ESM.pdf (314 kb)
ESM 1 (PDF 314 kb).

References

  1. 1.
    Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–82. doi: 10.1002/ana.20501.CrossRefPubMedGoogle Scholar
  2. 2.
    Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134(Pt 6):1790–807. doi: 10.1093/brain/awr063.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28(6):1099–106. doi: 10.1002/stem.430.CrossRefPubMedGoogle Scholar
  4. 4.
    Savitz SI, Dinsmore J, Wu J, Henderson GV, Stieg P, Caplan LR. Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: a preliminary safety and feasibility study. Cerebrovasc Dis. 2005;20(2):101–7. doi: 10.1159/000086518.CrossRefPubMedGoogle Scholar
  5. 5.
    Savitz SI, Misra V, Kasam M, Juneja H, Cox CS Jr, Alderman S, et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011;70(1):59–69. doi: 10.1002/ana.22458.CrossRefPubMedGoogle Scholar
  6. 6.
    Sprigg N, Bath PM, Zhao L, Willmot MR, Gray LJ, Walker MF, et al. Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke. 2006;37(12):2979–83. doi: 10.1161/01.STR.0000248763.49831.c3.CrossRefPubMedGoogle Scholar
  7. 7.
    Bang OY. Clinical trials of adult stem cell therapy in patients with ischemic stroke. J Clin Neurol. 2016;12(1):14–20. doi: 10.3988/jcn.2016.12.1.14.CrossRefPubMedGoogle Scholar
  8. 8.
    Lindvall O, Kokaia Z. Recovery and rehabilitation in stroke: stem cells. Stroke. 2004;35(11 Suppl 1):2691–4. doi: 10.1161/01.STR.0000143323.84008.f4.CrossRefPubMedGoogle Scholar
  9. 9.
    Pendharkar AV, Chua JY, Andres RH, Wang N, Gaeta X, Wang H, et al. Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke. 2010;41(9):2064–70. doi: 10.1161/STROKEAHA.109.575993.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kang WJ, Kang HJ, Kim HS, Chung JK, Lee MC, Lee DS. Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J Nucl Med. 2006;47(8):1295–301.PubMedGoogle Scholar
  11. 11.
    Li WY, Choi YJ, Lee PH, Huh K, Kang YM, Kim HS, et al. Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. Cell Transplant. 2008;17(9):1045–59.CrossRefPubMedGoogle Scholar
  12. 12.
    Kim SJ, Moon GJ, Chang WH, Kim YH, Bang OY. Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial. Trials. 2013;14(1):317. doi: 10.1186/1745-6215-14-317.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shin JH, Park YM, Kim DH, Moon GJ, Bang OY, Ohn T, et al. Ischemic brain extract increases SDF-1 expression in astrocytes through the CXCR2/miR-223/miR-27b pathway. Biochim Biophys Acta. 2014;1839(9):826–36. doi: 10.1016/j.bbagrm.2014.06.019.CrossRefPubMedGoogle Scholar
  14. 14.
    Kim DH, Seo YK, Thambi T, Moon GJ, Son JP, Li G, et al. Enhancing neurogenesis and angiogenesis with target delivery of stromal cell derived factor-1alpha using a dual ionic pH-sensitive copolymer. Biomaterials. 2015;61:115–25. doi: 10.1016/j.biomaterials.2015.05.025.CrossRefPubMedGoogle Scholar
  15. 15.
    Moon GJ, Shin DH, Im DS, Bang OY, Nam HS, Lee JH, et al. Identification of oxidized serum albumin in the cerebrospinal fluid of ischaemic stroke patients. Eur J Neurol. 2011;18(9):1151–8. doi: 10.1111/j.1468-1331.2011.03357.x.CrossRefPubMedGoogle Scholar
  16. 16.
    Zacharek A, Shehadah A, Chen J, Cui X, Roberts C, Lu M, et al. Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke. 2010;41(3):524–30. doi: 10.1161/STROKEAHA.109.568881.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rosado-de-Castro PH, Schmidt Fda R, Battistella V, Lopes de Souza SA, Gutfilen B, Goldenberg RC et al. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen Med 2013;8(2):145–155. doi: 10.2217/rme.13.2.
  18. 18.
    Rosenblum S, Wang N, Smith TN, Pendharkar AV, Chua JY, Birk H, et al. Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. Stroke. 2012;43(6):1624–31. doi: 10.1161/STROKEAHA.111.637884.CrossRefPubMedGoogle Scholar
  19. 19.
    Dimmeler S, Ding S, Rando TA, Trounson A. Translational strategies and challenges in regenerative medicine. Nat Med. 2014;20(8):814–21. doi: 10.1038/nm.3627.CrossRefPubMedGoogle Scholar
  20. 20.
    Yang B, Migliati E, Parsha K, Schaar K, Xi X, Aronowski J, et al. Intra-arterial delivery is not superior to intravenous delivery of autologous bone marrow mononuclear cells in acute ischemic stroke. Stroke. 2013;44(12):3463–72. doi: 10.1161/STROKEAHA.111.000821.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bang OY, Jin KS, Hwang MN, Kang HY, Kim BJ, Lee SJ, et al. The effect of CXCR4 overexpression on mesenchymal stem cell transplantation in ischemic stroke. Cell Med. 2012;4:65–76.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cutler C, Multani P, Robbins D, Kim HT, Le T, Hoggatt J, et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013;122(17):3074–81. doi: 10.1182/blood-2013-05-503177.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4(4):313–23. doi: 10.1016/j.stem.2009.02.013.CrossRefPubMedGoogle Scholar
  24. 24.
    Cui X, Chen J, Zacharek A, Li Y, Roberts C, Kapke A, et al. Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke. Stem Cells. 2007;25(11):2777–85. doi: 10.1634/stemcells.2007-0169.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pons J, Huang Y, Arakawa-Hoyt J, Washko D, Takagawa J, Ye J, et al. VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem Biophys Res Commun. 2008;376(2):419–22. doi: 10.1016/j.bbrc.2008.09.003.CrossRefPubMedGoogle Scholar
  26. 26.
    Liu H, Xue W, Ge G, Luo X, Li Y, Xiang H, et al. Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1alpha in MSCs. Biochem Biophys Res Commun. 2010;401(4):509–15. doi: 10.1016/j.bbrc.2010.09.076.CrossRefPubMedGoogle Scholar
  27. 27.
    Francis KR, Wei L. Human embryonic stem cell neural differentiation and enhanced cell survival promoted by hypoxic preconditioning. Cell Death Dis. 2010;1:e22. doi: 10.1038/cddis.2009.22.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hu X, Yu SP, Fraser JL, Lu Z, Ogle ME, Wang JA, et al. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg. 2008;135(4):799–808. doi: 10.1016/j.jtcvs.2007.07.071.CrossRefPubMedGoogle Scholar
  29. 29.
    Theus MH, Wei L, Cui L, Francis K, Hu X, Keogh C, et al. In vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain. Exp Neurol. 2008;210(2):656–70. doi: 10.1016/j.expneurol.2007.12.020.CrossRefPubMedGoogle Scholar
  30. 30.
    Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, Ashraf M. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res. 2008;77(1):134–42. doi: 10.1093/cvr/cvm025.CrossRefPubMedGoogle Scholar
  31. 31.
    Ancelin M, Chollet-Martin S, Herve MA, Legrand C, El Benna J, Perrot-Applanat M. Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism. Lab Investig. 2004;84(4):502–12. doi: 10.1038/labinvest.3700053.CrossRefPubMedGoogle Scholar
  32. 32.
    Zigmond SH, Hirsch JG. Leukocyte locomotion and chemotaxis. New methods for evaluation, and demonstration of a cell-derived chemotactic factor. J Exp Med. 1973;137(2):387–410.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ehrenfeld P, Millan C, Matus CE, Figueroa JE, Burgos RA, Nualart F, et al. Activation of kinin B1 receptors induces chemotaxis of human neutrophils. J Leukoc Biol. 2006;80(1):117–24. doi: 10.1189/jlb.1205744.CrossRefPubMedGoogle Scholar
  34. 34.
    Deng C, Qin A, Zhao W, Feng T, Shi C, Liu T. Up-regulation of CXCR4 in rat umbilical mesenchymal stem cells induced by serum from rat with acute liver failure promotes stem cells migration to injured liver tissue. Mol Cell Biochem. 2014; doi: 10.1007/s11010-014-2147-7.
  35. 35.
    Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells. 2006;24(5):1254–64. doi: 10.1634/stemcells.2005-0271.CrossRefPubMedGoogle Scholar
  36. 36.
    Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells. 2006;24(4):1030–41. doi: 10.1634/stemcells.2005-0319.CrossRefPubMedGoogle Scholar
  37. 37.
    Li Y, Yu X, Lin S, Li X, Zhang S, Song YH. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells. Biochem Biophys Res Commun. 2007;356(3):780–4. doi: 10.1016/j.bbrc.2007.03.049.CrossRefPubMedGoogle Scholar
  38. 38.
    Bhakta S, Hong P, Koc O. The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation. Cardiovas Revasc Med. 2006;7(1):19–24. doi: 10.1016/j.carrev.2005.10.008.CrossRefGoogle Scholar
  39. 39.
    Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model. Circulation. 1997;95(11):2552–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J, et al. Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology. 2002;22(4):275–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Tacchini L, De Ponti C, Matteucci E, Follis R, Desiderio MA. Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines. Carcinogenesis. 2004;25(11):2089–100. doi: 10.1093/carcin/bgh227.CrossRefPubMedGoogle Scholar
  42. 42.
    Tacchini L, Dansi P, Matteucci E, Desiderio MA. Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis. 2001;22(9):1363–71.CrossRefPubMedGoogle Scholar
  43. 43.
    Kohler T, Reizis B, Johnson RS, Weighardt H, Forster I. Influence of hypoxia-inducible factor 1alpha on dendritic cell differentiation and migration. Eur J Immunol. 2012;42(5):1226–36. doi: 10.1002/eji.201142053.CrossRefPubMedGoogle Scholar
  44. 44.
    Choi JH, Lee YB, Jung J, Hwang SG, Oh IH, Kim GJ. Hypoxia inducible factor-1alpha regulates the migration of bone marrow mesenchymal stem cells via integrin alpha 4. Stem Cells Int. 2016;2016:7932185. doi: 10.1155/2016/7932185.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hot A, Zrioual S, Lenief V, Miossec P. IL-17 and tumour necrosis factor alpha combination induces a HIF-1alpha-dependent invasive phenotype in synoviocytes. Ann Rheum Dis. 2012;71(8):1393–401. doi: 10.1136/annrheumdis-2011-200867.CrossRefPubMedGoogle Scholar
  46. 46.
    Scharte M, Han X, Bertges DJ, Fink MP, Delude RL. Cytokines induce HIF-1 DNA binding and the expression of HIF-1-dependent genes in cultured rat enterocytes. Am J Physiol Gastrointest Liver Physiol. 2003;284(3):G373–84. doi: 10.1152/ajpgi.00076.2002.CrossRefPubMedGoogle Scholar
  47. 47.
    Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res. 2006;66(8):4249–55. doi: 10.1158/0008-5472.CAN-05-2789.CrossRefPubMedGoogle Scholar
  48. 48.
    Shi YH, Wang YX, Bingle L, Gong LH, Heng WJ, Li Y, et al. In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol. 2005;205(4):530–6. doi: 10.1002/path.1734.CrossRefPubMedGoogle Scholar
  49. 49.
    Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000;60(6):1541–5.PubMedGoogle Scholar
  50. 50.
    Slomiany MG, Rosenzweig SA. IGF-1-induced VEGF and IGFBP-3 secretion correlates with increased HIF-1 alpha expression and activity in retinal pigment epithelial cell line D407. Invest Ophthalmol Vis Sci. 2004;45(8):2838–47. doi: 10.1167/iovs.03-0565.CrossRefPubMedGoogle Scholar
  51. 51.
    McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006;281(34):24171–81. doi: 10.1074/jbc.M604507200.CrossRefPubMedGoogle Scholar
  52. 52.
    Chu SH, Ma YB, Zhang H, Feng DF, Zhu ZA, Li ZQ, et al. Hepatocyte growth factor production is stimulated by gangliosides and TGF-beta isoforms in human glioma cells. J Neuro-Oncol. 2007;85(1):33–8. doi: 10.1007/s11060-007-9387-2.CrossRefGoogle Scholar
  53. 53.
    Lewis MP, Lygoe KA, Nystrom ML, Anderson WP, Speight PM, Marshall JF, et al. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer. 2004;90(4):822–32. doi: 10.1038/sj.bjc.6601611.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Takami Y, Motoki T, Yamamoto I, Gohda E. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferon-gamma. Biochem Biophys Res Commun. 2005;327(1):212–7. doi: 10.1016/j.bbrc.2004.11.144.CrossRefPubMedGoogle Scholar
  55. 55.
    Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Investig. 2006;86(12):1221–32. doi: 10.1038/labinvest.3700482.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhao Y, Matsuo-Takasaki M, Tsuboi I, Kimura K, Salazar GT, Yamashita T, et al. Dual functions of hypoxia-inducible factor 1 alpha for the commitment of mouse embryonic stem cells toward a neural lineage. Stem Cells Dev. 2014;23(18):2143–55. doi: 10.1089/scd.2013.0278.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Oh Young Bang
    • 1
    • 2
    • 3
    Email author
  • Gyeong Joon Moon
    • 3
    • 4
  • Dong Hee Kim
    • 2
    • 3
  • Ji Hyun Lee
    • 2
    • 3
  • Sooyoon Kim
    • 3
  • Jeong Pyo Son
    • 2
    • 3
  • Yeon Hee Cho
    • 3
  • Won Hyuk Chang
    • 5
  • Yun-Hee Kim
    • 5
  • the STARTING-2 trial investigators
  1. 1.Departments of Neurology, Samsung Medical CenterSungkyunkwan UniversitySeoulSouth Korea
  2. 2.Samsung Advanced Institute for Health Sciences and TechnologySungkyunkwan UniversitySeoulSouth Korea
  3. 3.Translational and Stem Cell Research Laboratory on StrokeSamsung Medical CenterSeoulSouth Korea
  4. 4.Stem Cell and Regenerative Medicine InstituteSamsung Medical CenterSeoulSouth Korea
  5. 5.Department of Physical and Rehabilitation Medicine, Samsung Medical CenterSungkyunkwan UniversitySeoulSouth Korea

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