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Induction of Perivascular Neural Stem Cells and Possible Contribution to Neurogenesis Following Transient Brain Ischemia/Reperfusion Injury

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Abstract

Recent therapeutic advances have increased the likelihood of recanalizing the obstructed brain arteries in patients with stroke. Therefore, it is important to understand the fate of neural cells under transient ischemia/reperfusion injury. Accumulating evidence shows that neurogenesis occurs in perivascular regions following brain injury, although the precise mechanism and origin of these newborn neurons under transient ischemia/reperfusion injury remain unclear. Using a mouse model of transient brain ischemia/reperfusion injury, we found that neural stem cells (NSCs) develop within injured areas. This induction of NSCs following ischemia/reperfusion injury was observed even in response to nonlethal ischemia, although massive numbers of NSCs were induced by lethal ischemia. Immunohistochemical and immunoelectron microscopic studies indicated that platelet-derived growth factor receptor beta-positive (PDGFRβ+) pericytes within injured areas following nonlethal ischemia began to express the NSC marker nestin as early as 3 days after transient ischemia/reperfusion. Some PDGFRβ+ pericytes expressed the immature neuronal marker doublecortin at day 7. These findings indicate that brain pericytes are a potential source of the perivascular NSCs that generate neuronal cells under lethal and nonlethal ischemic conditions following transient ischemia/reperfusion. Thus, brain pericytes might be a target for neurogenesis mediation in patients with nonlethal and lethal ischemia following transient ischemia/reperfusion injury.

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References

  1. Mokin M, Kass-Hout T, Kass-Hout O, Dumont TM, Kan P, Snyder KV, et al. Intravenous thrombolysis and endovascular therapy for acute ischemic stroke with internal carotid artery occlusion: a systematic review of clinical outcomes. Stroke. 2012;43(9):2362–8.

    Article  CAS  PubMed  Google Scholar 

  2. Zaidat OO, Suarez JI, Sunshine JL, Tarr RW, Alexander MJ, Smith TP, et al. Thrombolytic therapy of acute ischemic stroke: correlation of angiographic recanalization with clinical outcome. AJNR Am J Neuroradiol. 2005;26(4):880–4.

    PubMed  Google Scholar 

  3. Nakano-Doi A, Nakagomi T, Fujikawa M, Nakagomi N, Kubo S, Lu S, et al. Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction. Stem Cells. 2010;28(7):1292–302.

    CAS  PubMed  Google Scholar 

  4. Nakagomi N, Nakagomi T, Kubo S, Nakano-Doi A, Saino O, Takata M, et al. Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction. Stem Cells. 2009;27(9):2185–95.

    Article  PubMed  Google Scholar 

  5. Nakayama D, Matsuyama T, Ishibashi-Ueda H, Nakagomi T, Kasahara Y, Hirose H, et al. Injury-induced neural stem/progenitor cells in post-stroke human cerebral cortex. Eur J Neurosci. 2010;31(1):90–8.

    Article  PubMed  Google Scholar 

  6. Alvarez-Buylla A, Garcia-Verdugo JM. Neurogenesis in adult subventricular zone. J Neurosci. 2002;22(3):629–34.

    CAS  PubMed  Google Scholar 

  7. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16(6):2027–33.

    CAS  PubMed  Google Scholar 

  8. Nakagomi T, Taguchi A, Fujimori Y, Saino O, Nakano-Doi A, Kubo S, et al. Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice. Eur J Neurosci. 2009;29(9):1842–52.

    Article  PubMed  Google Scholar 

  9. Nakagomi T, Molnar Z, Taguchi A, Nakano-Doi A, Lu S, Kasahara Y, et al. Leptomeningeal-derived doublecortin-expressing cells in poststroke brain. Stem Cells Dev. 2012;21(13):2350–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nakagomi T, Molnar Z, Nakano-Doi A, Taguchi A, Saino O, Kubo S, et al. Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction. Stem Cells Dev. 2011;20(12):2037–51.

    Article  CAS  PubMed  Google Scholar 

  11. Nakagomi T, Nakano-Doi A, Matsuyama T. Leptomeninges: a novel stem cell niche harboring ischemia-induced neural progenitors. Histol Histopathol. 2015;30:391–9.

    CAS  PubMed  Google Scholar 

  12. Nakagomi T, Kubo S, Nakano-Doi A, Sakuma R, Lu S, Narita A, et al. Brain vascular pericytes following ischemia have multipotential stem cell activity to differntiate into neural and vascular lineage cells. Stem Cells. 2015;33(6):1962–74.

    Article  CAS  PubMed  Google Scholar 

  13. Ohira K, Furuta T, Hioki H, Nakamura KC, Kuramoto E, Tanaka Y, et al. Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells. Nat Neurosci. 2010;13(2):173–9.

    Article  CAS  PubMed  Google Scholar 

  14. Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest. 2004;114(3):330–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Taguchi A, Wen Z, Myojin K, Yoshihara T, Nakagomi T, Nakayama D, et al. Granulocyte colony-stimulating factor has a negative effect on stroke outcome in a murine model. Eur J Neurosci. 2007;26(1):126–33.

    Article  PubMed  Google Scholar 

  16. Tamura A, Gotoh O, Sano K. Focal cerebral infarction in the rat: I. Operative technique and physiological monitorings for chronic model. No To Shinkei. 1986;38(8):747–51.

    CAS  PubMed  Google Scholar 

  17. Kasahara Y, Ihara M, Nakagomi T, Momota Y, Stern DM, Matsuyama T, et al. A highly reproducible model of cerebral ischemia/reperfusion with extended survival in CB-17 mice. Neurosci Res. 2013;76(3):163–8.

    Article  PubMed  Google Scholar 

  18. Kasahara Y, Nakagomi T, Matsuyama T, Stern D, Taguchi A. Cilostazol reduces the risk of hemorrhagic infarction after administration of tissue-type plasminogen activator in a murine stroke model. Stroke. 2012;43(2):499–506.

    Article  CAS  PubMed  Google Scholar 

  19. Taguchi A, Kasahara Y, Nakagomi T, Stern DM, Fukunaga M, Ishikawa M, et al. A reproducible and simple model of permanent cerebral ischemia in CB-17 and SCID Mice. J Exp Stroke Transl Med. 2010;3(1):28–33.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Saino O, Taguchi A, Nakagomi T, Nakano-Doi A, Kashiwamura S, Doe N, et al. Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J Neurosci Res. 2010;88(11):2385–97.

    CAS  PubMed  Google Scholar 

  21. Zille M, Farr TD, Przesdzing I, Muller J, Sommer C, Dirnagl U, et al. Visualizing cell death in experimental focal cerebral ischemia: promises, problems, and perspectives. J Cereb Blood Flow Metab. 2012;32(2):213–31.

    Article  PubMed  Google Scholar 

  22. Shimada IS, Peterson BM, Spees JL. Isolation of locally derived stem/progenitor cells from the peri-infarct area that do not migrate from the lateral ventricle after cortical stroke. Stroke. 2010;41(9):e552–60.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zaidat OO, Suarez JI, Santillan C, Sunshine JL, Tarr RW, Paras VH, et al. Response to intra-arterial and combined intravenous and intra-arterial thrombolytic therapy in patients with distal internal carotid artery occlusion. Stroke. 2002;33(7):1821–6.

    Article  CAS  PubMed  Google Scholar 

  24. Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res. 2000;60(1):55–69.

    Article  CAS  PubMed  Google Scholar 

  25. Kabara M, Kawabe J, Matsuki M, Hira Y, Minoshima A, Shimamura K, et al. Immortalized multipotent pericytes derived from the vasa vasorum in the injured vasculature. A cellular tool for studies of vascular remodeling and regeneration. Lab Invest. 2014;94(12):1340–54.

    Article  CAS  PubMed  Google Scholar 

  26. Tsang WP, Shu Y, Kwok PL, Zhang F, Lee KK, Tang MK, et al. CD146+ human umbilical cord perivascular cells maintain stemness under hypoxia and as a cell source for skeletal regeneration. PLoS One. 2013;8(10):e76153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen CW, Okada M, Proto JD, Gao X, Sekiya N, Beckman SA, et al. Human pericytes for ischemic heart repair. Stem Cells. 2013;31(2):305–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab. 2006;26(5):613–24.

    Article  CAS  PubMed  Google Scholar 

  29. Birbrair A, Zhang T, Wang ZM, Messi ML, Enikolopov GN, Mintz A, et al. Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res. 2012;10(1):67–84.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dar A, Domev H, Ben-Yosef O, Tzukerman M, Zeevi-Levin N, Novak A, et al. Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation. 2012;125(1):87–99.

    Article  PubMed  Google Scholar 

  31. Sakuma R, Kawahara M, Nakano-Doi A, Takahashi A, Tanaka Y, Narita A, et al. Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. J Neuroinflammation. 2016;13(1):57.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Karow M, Sanchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, et al. Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell. 2012;11(4):471–6.

    Article  CAS  PubMed  Google Scholar 

  33. Nakagomi T, Nakano-Doi A, Kawamura M, Matsuyama T. Do vascular pericytes contribute to neurovasculogenesis in the central nervous system as multipotent vascular stem cells? Stem Cells Dev. 2015;24(15):1730–9.

    Article  PubMed  Google Scholar 

  34. Nakagomi T, Nakano-Doi A, Narita A, Matsuyama T. Concise review: are stimulated somatic cells truly reprogrammed into an ES/iPS-like pluripotent state? Better understanding by ischemia-induced multipotent stem cells in a mouse model of cerebral infarction. Stem Cells Int. 2015;2015:630693.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Jiao J, Chen DF. Induction of neurogenesis in nonconventional neurogenic regions of the adult central nervous system by niche astrocyte-produced signals. Stem Cells. 2008;26(5):1221–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Banerjee S, Bhat MA. Neuron-glial interactions in blood–brain barrier formation. Annu Rev Neurosci. 2007;30:235–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was partially supported by JSPS KAKENHI Grant Numbers (24650173, 15K09329, 25463159), grant-in-aid for researchers, Hyogo College of Medicine (2013), and Osaka Dental University Research Funds (2014). We would like to thank Y. Tokumitsu, R. Sakuma, and Y. Tanaka for helpful assistance and discussions.

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Authors and Affiliations

  1. Institute for Advanced Medical Sciences, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, 663-8501, Hyogo, Japan

    Masayo Nakata, Takayuki Nakagomi, Akiko Nakano-Doi & Tomohiro Matsuyama

  2. Department of Anesthesiology, Osaka Dental University, 1-5-17 Otemae, Chuo-ku, Osaka, 540-0008, Osaka, Japan

    Masayo Nakata & Yoshihiro Momota

  3. Multi-Modal Microstructure Analysis Unit, RIKEN CLST-JEOL Collaboration Center, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Hyogo, Japan

    Mitsuyo Maeda

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  1. Masayo Nakata
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  2. Takayuki Nakagomi
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  3. Mitsuyo Maeda
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  4. Akiko Nakano-Doi
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  5. Yoshihiro Momota
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  6. Tomohiro Matsuyama
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Corresponding authors

Correspondence to Takayuki Nakagomi or Yoshihiro Momota.

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All procedure performed in this study involving animal experiments were in accordance with the ethical standards as described in the methods sections.

Conflict of Interest

The authors declare that that have no conflict of interest.

Authors’ Contributions

MN: collection and assembly of data, financial support, and data analysis and interpretation; TN: conception and design, financial support, data analysis and interpretation, and manuscript writing and editing; MM: collection and assembly of data, data analysis and interpretation, and manuscript writing; AN-D: collection and assembly of data; YM: conception and design, financial support, collection and assembly of data, data analysis and interpretation, and manuscript writing; TM: conception and design, financial support, and data analysis and interpretation. All authors read and approved the final manuscript.

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Nakata, M., Nakagomi, T., Maeda, M. et al. Induction of Perivascular Neural Stem Cells and Possible Contribution to Neurogenesis Following Transient Brain Ischemia/Reperfusion Injury. Transl. Stroke Res. 8, 131–143 (2017). https://doi.org/10.1007/s12975-016-0479-1

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  • DOI: https://doi.org/10.1007/s12975-016-0479-1

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