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Mesenchymal Stromal Cell Therapy of Stroke

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Cellular and Molecular Approaches to Regeneration and Repair

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Stroke is a major cause of high mortality, morbidity and long-term disability worldwide. Development of neuroprotective and neurorestorative therapies for stroke has been a target of intense research. Accumulating preclinical literature has identified that bone marrow mesenchymal stromal cell (MSC) treatment of stroke improves neurological functional outcome after stroke. This chapter focuses on the therapeutic effects and molecular mechanisms underlying MSC treatment of stroke, such as angiogenesis, arteriogenesis, neurogenesis and white matter remodeling, as well as a discussion on the interaction/coupling among these restorative events. In addition, the role of microRNAs (miRNAs) and MSC secreted exosomes in mediating intercellular communication between MSCs and parenchymal cells of the brain, and their effects on the regulation of neurovascular remodeling and white matter remodeling after stroke are discussed.

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Abbreviations

BBB:

Brain-blood barrier

BDNF:

Brain-derived neurotrophic factor

BMMNC:

Autologous bone marrow mononuclear cell

CRT:

Corticorubral tract

CST:

Corticospinal tract

DM:

Diabetes mellitus

FGF-2:

Fibroblast growth factor-2

GDNF:

Glial cell line-derived neurotrophic factor

HGF:

Hepatocyte growth factor

HLA-DR:

Human leukocyte antigen-antigen D related

IA:

Intra-arterial

IC:

Intracerebral

ICH:

Intracerebral hemorrhage

ICV:

Intracerebro ventricular

IGF:

Insulin-like growth factor

IN:

Intranasal

IV:

Intravenous

miRNA:

MicroRNA

MSC:

Mesenchymal stromal cell

MSC-Exo:

Exosome derived from MSCs

mTOR:

Mammalian target of rapamycin

NGF:

Nerve growth factor

NPCs:

Neural progenitor cells

NSCs:

Neural stem cells

OPC:

Oligodendrocyte progenitor cell

PGF:

Placental growth factor

PTEN:

Phosphatase and tensin homologue

SHRSP:

Spontaneously hypertensive stroke prone

T1DM:

Type 1 diabetic

tPA:

Tissue plasminogen activator

VEGF:

Vascular endothelial growth factor

References

  1. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42(7):1952–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chen J, Chopp M. Neurorestorative treatment of stroke: cell and pharmacological approaches. NeuroRx. 2006;3(4):466–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen J, Venkat P, Zacharek A, Chopp M. Neurorestorative therapy for stroke. Front Hum Neurosci. 2014;8:382.

    PubMed  PubMed Central  Google Scholar 

  4. Liu X, Ye R, Yan T, Yu SP, Wei L, Xu G, et al. Cell based therapies for ischemic stroke: from basic science to bedside. Prog Neurobiol. 2014;115:92–115.

    Article  PubMed  Google Scholar 

  5. Mazzini L, Mareschi K, Ferrero I, Miglioretti M, Stecco A, Servo S, et al. Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy. 2012;14(1):56–60.

    Article  PubMed  Google Scholar 

  6. 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;14:317.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81(10):1390–7.

    Article  PubMed  Google Scholar 

  8. Krause DS. Plasticity of marrow-derived stem cells. Gene Ther. 2002;9(11):754–8.

    Article  CAS  PubMed  Google Scholar 

  9. Menasche P. Cell transplantation for the treatment of heart failure. Semin Thorac Cardiovasc Surg. 2002;14(2):157–66.

    Article  PubMed  Google Scholar 

  10. Wang JS, Shum-Tim D, Galipeau J, Chedrawy E, Eliopoulos N, Chiu RC. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg. 2000;120(5):999–1005.

    Article  CAS  PubMed  Google Scholar 

  11. Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci. 2001;189(1–2):49–57.

    Article  CAS  PubMed  Google Scholar 

  12. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002;59(4):514–23.

    Article  CAS  PubMed  Google Scholar 

  13. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3(4):393–403.

    CAS  PubMed  Google Scholar 

  14. Si YL, Zhao YL, Hao HJ, Fu XB, Han WD. MSCs: biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev. 2011;10(1):93–103.

    Article  CAS  PubMed  Google Scholar 

  15. Ye X, Hu J, Cui G. Therapy effects of bone marrow stromal cells on ischemic stroke. Oxidative Med Cell Longev. 2016;2016:7682960.

    Google Scholar 

  16. Nombela-Arrieta C, Ritz J, Silberstein LE. The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol. 2011;12(2):126–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.

    Article  CAS  PubMed  Google Scholar 

  18. Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: isolation, expansion and differentiation. Methods. 2008;45(2):115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Futami I, Ishijima M, Kaneko H, Tsuji K, Ichikawa-Tomikawa N, Sadatsuki R, et al. Isolation and characterization of multipotential mesenchymal cells from the mouse synovium. PLoS One. 2012;7(9):e45517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119(Pt 11):2204–13.

    Article  PubMed  CAS  Google Scholar 

  22. Dezawa M, Ishikawa H, Hoshino M, Itokazu Y, Nabeshima Y. Potential of bone marrow stromal cells in applications for neuro-degenerative, neuro-traumatic and muscle degenerative diseases. Curr Neuropharmacol. 2005;3(4):257–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ. Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood. 2004;103(5):1662–8.

    Article  CAS  PubMed  Google Scholar 

  24. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, et al. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003;92(6):692–9.

    Article  CAS  PubMed  Google Scholar 

  25. Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell. 2000;100(1):157–68.

    Article  CAS  PubMed  Google Scholar 

  26. Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, et al. Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab. 2000;20(9):1311–9.

    Article  CAS  PubMed  Google Scholar 

  27. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000;164(2):247–56.

    Article  CAS  PubMed  Google Scholar 

  28. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A. 1999;96(19):10711–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001;32(4):1005–11.

    Article  CAS  PubMed  Google Scholar 

  30. Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002;174(1):11–20.

    Article  PubMed  Google Scholar 

  31. Weng JS, Liu N, Du HW, Chen RH, Zhang YX, Wang JH, et al. Effects of bone marrow-derived mesenchymal stem cells transplantation on recovery of neurological functions and expression of synaptophysin in focal cerebral infarction in rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2008;24(1):34–7.

    CAS  PubMed  Google Scholar 

  32. Huang W, Mo X, Qin C, Zheng J, Liang Z, Zhang C. Transplantation of differentiated bone marrow stromal cells promotes motor functional recovery in rats with stroke. Neurol Res. 2013;35(3):320–8.

    Article  PubMed  CAS  Google Scholar 

  33. Pavlichenko N, Sokolova I, Vijde S, Shvedova E, Alexandrov G, Krouglyakov P, et al. Mesenchymal stem cells transplantation could be beneficial for treatment of experimental ischemic stroke in rats. Brain Res. 2008;1233:203–13.

    Article  CAS  PubMed  Google Scholar 

  34. Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259(2):150–6.

    Article  CAS  PubMed  Google Scholar 

  35. Scheibe F, Ladhoff J, Huck J, Grohmann M, Blazej K, Oersal A, et al. Immune effects of mesenchymal stromal cells in experimental stroke. J Cereb Blood Flow Metab. 2012;32(8):1578–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73(6):778–86.

    Article  CAS  PubMed  Google Scholar 

  37. Tohill M, Mantovani C, Wiberg M, Terenghi G. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett. 2004;362(3):200–3.

    Article  CAS  PubMed  Google Scholar 

  38. Al-Khaldi A, Eliopoulos N, Martineau D, Lejeune L, Lachapelle K, Galipeau J. Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo. Gene Ther. 2003;10(8):621–9.

    Article  CAS  PubMed  Google Scholar 

  39. Cui X, Chopp M, Zacharek A, Roberts C, Lu M, Savant-Bhonsale S, et al. Chemokine, vascular and therapeutic effects of combination Simvastatin and BMSC treatment of stroke. Neurobiol Dis. 2009;36(1):35–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, et al. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab. 2007;27(1):6–13.

    Article  PubMed  CAS  Google Scholar 

  41. Park WS, Sung SI, Ahn SY, Sung DK, Im GH, Yoo HS, et al. Optimal timing of mesenchymal stem cell therapy for neonatal intraventricular hemorrhage. Cell Transplant. 2016;25(6):1131–44.

    Article  PubMed  Google Scholar 

  42. Rosado-de-Castro PH, de Carvalho FG, de Freitas GR, Mendez-Otero R, Pimentel-Coelho PM. Review of preclinical and clinical studies of bone marrow-derived cell therapies for intracerebral hemorrhage. Stem Cells Int. 2016;2016:4617983.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Cui J, Cui C, Cui Y, Li R, Sheng H, Jiang X, et al. Bone marrow mesenchymal stem cell transplantation increases GAP-43 expression via ERK1/2 and PI3K/Akt pathways in intracerebral hemorrhage. Cell Physiol Biochem. 2017;42(1):137–44.

    Article  CAS  PubMed  Google Scholar 

  44. Ding R, Lin C, Wei S, Zhang N, Tang L, Lin Y, et al. Therapeutic benefits of mesenchymal stromal cells in a rat model of hemoglobin-induced hypertensive intracerebral hemorrhage. Mol Cells. 2017;40(2):133–42.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Otero L, Zurita M, Bonilla C, Aguayo C, Rico MA, Rodriguez A, et al. Allogeneic bone marrow stromal cell transplantation after cerebral hemorrhage achieves cell transdifferentiation and modulates endogenous neurogenesis. Cytotherapy. 2012;14(1):34–44.

    Article  CAS  PubMed  Google Scholar 

  46. Wang C, Fei Y, Xu C, Zhao Y, Pan Y. Bone marrow mesenchymal stem cells ameliorate neurological deficits and blood-brain barrier dysfunction after intracerebral hemorrhage in spontaneously hypertensive rats. Int J Clin Exp Pathol. 2015;8(5):4715–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang SP, Wang ZH, Peng DY, Li SM, Wang H, Wang XH. Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection. Mol Med Rep. 2012;6(4):848–54.

    Article  CAS  PubMed  Google Scholar 

  48. Khalili MA, Sadeghian-Nodoushan F, Fesahat F, Mir-Esmaeili SM, Anvari M, Hekmati-Moghadam SH. Mesenchymal stem cells improved the ultrastructural morphology of cerebral tissues after subarachnoid hemorrhage in rats. Exp Neurobiol. 2014;23(1):77–85.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Jolkkonen J, Kwakkel G. Translational hurdles in stroke recovery studies. Transl Stroke Res. 2016;7(4):331–42.

    Article  CAS  PubMed  Google Scholar 

  50. Pennypacker KR, Bix G, Fraser JF. Correcting the trajectory of stroke therapeutic research. Transl Stroke Res. 2017;8(1):65–6.

    Article  PubMed  Google Scholar 

  51. Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG, Howard G, et al. Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke. 2014;45(1):315–53.

    Article  PubMed  Google Scholar 

  52. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ghosh P, Sahoo R, Vaidya A, Chorev M, Halperin JA. Role of complement and complement regulatory proteins in the complications of diabetes. Endocr Rev. 2015;36(3):272–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vija L, Farge D, Gautier JF, Vexiau P, Dumitrache C, Bourgarit A, et al. Mesenchymal stem cells: stem cell therapy perspectives for type 1 diabetes. Diabetes Metab. 2009;35(2):85–93.

    Article  CAS  PubMed  Google Scholar 

  55. Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, et al. Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. Exp Neurol. 2011;232(2):299–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zang L, Hao H, Liu J, Li Y, Han W, Mu Y. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol Metab Syndr. 2017;9:36.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ding G, Chen J, Chopp M, Li L, Yan T, Li Q, et al. Cell treatment for stroke in type two diabetic rats improves vascular permeability measured by MRI. PLoS One. 2016;11(2):e0149147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Yan T, Ye X, Chopp M, Zacharek A, Ning R, Venkat P, et al. Niaspan attenuates the adverse effects of bone marrow stromal cell treatment of stroke in type one diabetic rats. PLoS One. 2013;8(11):e81199.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Chen J, Ye X, Yan T, Zhang C, Yang XP, Cui X, et al. Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke. 2011;42(12):3551–8.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Yan T, Venkat P, Chopp M, Zacharek A, Ning R, Roberts C, et al. Neurorestorative responses to delayed human mesenchymal stromal cells treatment of stroke in type 2 diabetic rats. Stroke. 2016;47(11):2850–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cui C, Ye X, Chopp M, Venkat P, Zacharek A, Yan T, et al. miR-145 regulates diabetes-bone marrow stromal cell-induced neurorestorative effects in diabetes stroke rats. Stem Cells Transl Med. 2016;5(12):1656–67.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Popa-Wagner A, Buga A-M, Doeppner TR, Hermann DM. Stem cell therapies in preclinical models of stroke associated with aging. Front Cell Neurosci. 2014;8:347.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Johansson BB. Hypertension mechanisms causing stroke. Clin Exp Pharmacol Physiol. 1999;26(7):563–5.

    Article  CAS  PubMed  Google Scholar 

  64. Calio ML, Marinho DS, Ko GM, Ribeiro RR, Carbonel AF, Oyama LM, et al. Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model. Free Radic Biol Med. 2014;70:141–54.

    Article  CAS  PubMed  Google Scholar 

  65. Chen C, Cheng Y, Chen J. Transfection of Noggin in bone marrow stromal cells (BMSCs) enhances BMSC-induced functional outcome after stroke in rats. J Neurosci Res. 2011;89(8):1194–202.

    Article  CAS  PubMed  Google Scholar 

  66. Zhao MZ, Nonoguchi N, Ikeda N, Watanabe T, Furutama D, Miyazawa D, et al. Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector. J Cereb Blood Flow Metab. 2006;26(9):1176–88.

    Article  CAS  PubMed  Google Scholar 

  67. Ding J, Cheng Y, Gao S, Chen J. Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res. 2011;89(2):222–30.

    Article  CAS  PubMed  Google Scholar 

  68. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31(12):2737–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ikeda N, Nonoguchi N, Zhao MZ, Watanabe T, Kajimoto Y, Furutama D, et al. Bone marrow stromal cells that enhanced fibroblast growth factor-2 secretion by herpes simplex virus vector improve neurological outcome after transient focal cerebral ischemia in rats. Stroke. 2005;36(12):2725–30.

    Article  CAS  PubMed  Google Scholar 

  70. Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Kobune M, Hirai S, et al. BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther. 2004;9(2):189–97.

    Article  CAS  PubMed  Google Scholar 

  71. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106(7):829–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yang C, Zhou L, Gao X, Chen B, Tu J, Sun H, et al. Neuroprotective effects of bone marrow stem cells overexpressing glial cell line-derived neurotrophic factor on rats with intracerebral hemorrhage and neurons exposed to hypoxia/reoxygenation. Neurosurgery. 2011;68(3):691–704.

    Article  PubMed  Google Scholar 

  73. Wei N, Yu SP, Gu X, Taylor TM, Song D, Liu XF, et al. Delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice. Cell Transplant. 2013;22(6):977–91.

    Article  PubMed  Google Scholar 

  74. Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, et al. Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther. 2011;2(5):38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang L, Lin Z, Shao B, Zhuge Q, Jin K. Therapeutic applications of bone marrow-derived stem cells in ischemic stroke. Neurol Res. 2013;35(5):470–8.

    Article  CAS  PubMed  Google Scholar 

  76. Misra V, Ritchie MM, Stone LL, Low WC, Janardhan V. Stem cell therapy in ischemic stroke: role of IV and intra-arterial therapy. Neurology. 2012;79(13 Suppl 1):S207–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yoo SW, Kim SS, Lee SY, Lee HS, Kim HS, Lee YD, et al. Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model. Exp Mol Med. 2008;40(4):387–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Irons H, Lind JG, Wakade CG, Yu G, Hadman M, Carroll J, et al. Intracerebral xenotransplantation of GFP mouse bone marrow stromal cells in intact and stroke rat brain: graft survival and immunologic response. Cell Transplant. 2004;13(3):283–94.

    Article  CAS  PubMed  Google Scholar 

  79. Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke. 2016;47(7):1817–24.

    Article  PubMed  Google Scholar 

  80. Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC, Elder E, Gebel J, et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg. 2005;103(1):38–45.

    Article  PubMed  Google Scholar 

  81. Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, et al. Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis. 2005;18(2):366–74.

    Article  CAS  PubMed  Google Scholar 

  82. Rabinovich SS, Seledtsov VI, Banul NV, Poveshchenko OV, Senyukov VV, Astrakov SV, et al. Cell therapy of brain stroke. Bull Exp Biol Med. 2005;139(1):126–8.

    Article  CAS  PubMed  Google Scholar 

  83. Jiang Q, Zhang ZG, Ding GL, Zhang L, Ewing JR, Wang L, et al. Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI. NeuroImage. 2005;28(3):698–707.

    Article  PubMed  Google Scholar 

  84. Modo M, Stroemer RP, Tang E, Patel S, Hodges H. Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage. Stroke. 2002;33(9):2270–8.

    Article  PubMed  Google Scholar 

  85. Chen JJ, Zhou SH. Mesenchymal stem cells overexpressing MiR-126 enhance ischemic angiogenesis via the AKT/ERK-related pathway. Cardiol J. 2011;18(6):675–81.

    Article  PubMed  Google Scholar 

  86. Guo F, Lv S, Lou Y, Tu W, Liao W, Wang Y, et al. Bone marrow stromal cells enhance the angiogenesis in ischaemic cortex after stroke: involvement of notch signalling. Cell Biol Int. 2012;36(11):997–1004.

    Article  CAS  PubMed  Google Scholar 

  87. Suarez-Monteagudo C, Hernandez-Ramirez P, Alvarez-Gonzalez L, Garcia-Maeso I, de la Cuetara-Bernal K, Castillo-Diaz L, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009;27(3):151–61.

    PubMed  Google Scholar 

  88. Wise AF, Williams TM, Kiewiet MB, Payne NL, Siatskas C, Samuel CS, et al. Human mesenchymal stem cells alter macrophage phenotype and promote regeneration via homing to the kidney following ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2014;306(10):F1222–35.

    Article  CAS  PubMed  Google Scholar 

  89. Bhasin A, Srivastava MV, Kumaran SS, Mohanty S, Bhatia R, Bose S, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra. 2011;1(1):93–104.

    Article  PubMed  PubMed Central  Google Scholar 

  90. 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.

    Article  PubMed  Google Scholar 

  91. Steiner B, Roch M, Holtkamp N, Kurtz A. Systemically administered human bone marrow-derived mesenchymal stem home into peripheral organs but do not induce neuroprotective effects in the MCAo-mouse model for cerebral ischemia. Neurosci Lett. 2012;513(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  92. Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, et al. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation. 2005;112(10):1451–61.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Li Y, Chen J, Wang L, Lu M, Chopp M. Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology. 2001;56(12):1666–72.

    Article  CAS  PubMed  Google Scholar 

  94. Byun JS, Kwak BK, Kim JK, Jung J, Ha BC, Park S. Engraftment of human mesenchymal stem cells in a rat photothrombotic cerebral infarction model: comparison of intra-arterial and intravenous infusion using MRI and histological analysis. J Korean Neurosurg Soc. 2013;54(6):467–76.

    Article  PubMed  PubMed Central  Google Scholar 

  95. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kamiya N, Ueda M, Igarashi H, Nishiyama Y, Suda S, Inaba T, et al. Intra-arterial transplantation of bone marrow mononuclear cells immediately after reperfusion decreases brain injury after focal ischemia in rats. Life Sci. 2008;83(11–12):433–7.

    Article  CAS  PubMed  Google Scholar 

  97. Dhuria SV, Hanson LR, Frey WH II. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654–73.

    Article  CAS  PubMed  Google Scholar 

  98. Jiang Y, Zhu J, Xu G, Liu X. Intranasal delivery of stem cells to the brain. Expert Opin Drug Deliv. 2011;8(5):623–32.

    Article  CAS  PubMed  Google Scholar 

  99. van Velthoven CT, Sheldon RA, Kavelaars A, Derugin N, Vexler ZS, Willemen HL, et al. Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke. 2013;44(5):1426–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Sun J, Wei ZZ, Gu X, Zhang JY, Zhang Y, Li J, et al. Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice. Exp Neurol. 2015;272:78–87.

    Article  CAS  PubMed  Google Scholar 

  101. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002;33(11):2675–80.

    Article  CAS  PubMed  Google Scholar 

  102. Pistoia V, Raffaghello L. Mesenchymal stromal cells and autoimmunity. Int Immunol. 2017;29(2):49–58.

    Article  CAS  PubMed  Google Scholar 

  103. Riess P, Zhang C, Saatman KE, Laurer HL, Longhi LG, Raghupathi R, et al. Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery. 2002;51(4):1043–52. discussion 52–4

    PubMed  Google Scholar 

  104. Van Damme A, Vanden Driessche T, Collen D, Chuah MK. Bone marrow stromal cells as targets for gene therapy. Curr Gene Ther. 2002;2(2):195–209.

    Article  PubMed  Google Scholar 

  105. Hanada K, Dennis JE, Caplan AI. Stimulatory effects of basic fibroblast growth factor and bone morphogenetic protein-2 on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. J Bone Miner Res. 1997;12(10):1606–14.

    Article  CAS  PubMed  Google Scholar 

  106. Martin DR, Cox NR, Hathcock TL, Niemeyer GP, Baker HJ. Isolation and characterization of multipotential mesenchymal stem cells from feline bone marrow. Exp Hematol. 2002;30(8):879–86.

    Article  CAS  PubMed  Google Scholar 

  107. Alberti-Amador E, Garcia-Miniet R. Bone marrow stromal cells. An alternative source of restorative therapy in degenerative diseases of the central nervous system. Rev Neurol. 2003;37(8):752–8.

    CAS  PubMed  Google Scholar 

  108. Prockop DJ, Gregory CA, Spees JL. One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci U S A. 2003;100(Suppl 1):11917–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shichinohe H, Kuroda S, Maruichi K, Osanai T, Sugiyama T, Chiba Y, et al. Bone marrow stromal cells and bone marrow-derived mononuclear cells: which are suitable as cell source of transplantation for mice infarct brain? Neuropathology. 2010;30(2):113–22.

    Article  PubMed  Google Scholar 

  110. Zhang J, Li Y, Zhang ZG, Lu M, Borneman J, Buller B, et al. Bone marrow stromal cells increase oligodendrogenesis after stroke. J Cereb Blood Flow Metab. 2009;29(6):1166–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shen LH, Li Y, Chen J, Cui Y, Zhang C, Kapke A, et al. One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke. Stroke. 2007;38(7):2150–6.

    Article  PubMed  Google Scholar 

  112. Chen J, Shehadah A, Pal A, Zacharek A, Cui X, Cui Y, et al. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell Transplant. 2012;22(5):871–9.

    Article  Google Scholar 

  113. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005;112(8):1128–35.

    Article  PubMed  Google Scholar 

  114. Ziegelhoeffer T, Fernandez B, Kostin S, Heil M, Voswinckel R, Helisch A, et al. Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res. 2004;94(2):230–8.

    Article  CAS  PubMed  Google Scholar 

  115. Hess DC, Abe T, Hill WD, Studdard AM, Carothers J, Masuya M, et al. Hematopoietic origin of microglial and perivascular cells in brain. Exp Neurol. 2004;186(2):134–44.

    Article  CAS  PubMed  Google Scholar 

  116. Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg. 2005;80(1):229–36. discussion 36–7

    Article  PubMed  Google Scholar 

  117. Kinnaird T, Stabile E, Burnett MS, Epstein SE. Bone marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res. 2004;95(4):354–63.

    Article  CAS  PubMed  Google Scholar 

  118. Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O, et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007;25(7):1737–45.

    Article  CAS  PubMed  Google Scholar 

  119. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648–59.

    Article  CAS  PubMed  Google Scholar 

  120. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94(5):678–85.

    Article  CAS  PubMed  Google Scholar 

  121. Matsuda-Hashii Y, Takai K, Ohta H, Fujisaki H, Tokimasa S, Osugi Y, et al. Hepatocyte growth factor plays roles in the induction and autocrine maintenance of bone marrow stromal cell IL-11, SDF-1 alpha, and stem cell factor. Exp Hematol. 2004;32(10):955–61.

    Article  CAS  PubMed  Google Scholar 

  122. Annabi B, Lee YT, Turcotte S, Naud E, Desrosiers RR, Champagne M, et al. Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation. Stem Cells. 2003;21(3):337–47.

    Article  CAS  PubMed  Google Scholar 

  123. Eaves CJ, Cashman JD, Kay RJ, Dougherty GJ, Otsuka T, Gaboury LA, et al. Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. II. Analysis of positive and negative regulators produced by stromal cells within the adherent layer. Blood. 1991;78(1):110–7.

    CAS  PubMed  Google Scholar 

  124. Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol. 1998;176(1):57–66.

    Article  CAS  PubMed  Google Scholar 

  125. Seshi B, Kumar S, Sellers D. Human bone marrow stromal cell: coexpression of markers specific for multiple mesenchymal cell lineages. Blood Cells Mol Dis. 2000;26(3):234–46.

    Article  CAS  PubMed  Google Scholar 

  126. Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol. 1999;58(4):313–20.

    Article  CAS  PubMed  Google Scholar 

  127. Renner O, Tsimpas A, Kostin S, Valable S, Petit E, Schaper W, et al. Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia. Brain Res Mol Brain Res. 2003;113(1–2):44–51.

    Article  CAS  PubMed  Google Scholar 

  128. Slevin M, Kumar P, Gaffney J, Kumar S, Krupinski J. Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential. Clin Sci (Lond). 2006;111(3):171–83.

    Article  CAS  Google Scholar 

  129. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25(9):1794–8.

    Article  CAS  PubMed  Google Scholar 

  130. Wei L, Erinjeri JP, Rovainen CM, Woolsey TA. Collateral growth and angiogenesis around cortical stroke. Stroke. 2001;32(9):2179–84.

    Article  CAS  PubMed  Google Scholar 

  131. Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, et al. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther. 2014;143(2):181–96.

    Article  CAS  PubMed  Google Scholar 

  132. Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, et al. Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007;27(10):1684–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Nam HS, Kwon I, Lee BH, Kim H, Kim J, An S, et al. Effects of mesenchymal stem cell treatment on the expression of matrix metalloproteinases and angiogenesis during ischemic stroke recovery. PLoS One. 2015;10(12):e0144218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Doeppner TR, Hermann DM. Mesenchymal stem cells in the treatment of ischemic stroke: progress and possibilities. Stem Cells Cloning. 2010;3:157–63.

    PubMed  PubMed Central  Google Scholar 

  135. Jiang Q, Zhang ZG, Ding GL, Silver B, Zhang L, Meng H, et al. MRI detects white matter reorganization after neural progenitor cell treatment of stroke. NeuroImage. 2006;32(3):1080–9.

    Article  PubMed  Google Scholar 

  136. Zhang R, Chopp M, Zhang ZG. Oligodendrogenesis after cerebral ischemia. Front Cell Neurosci. 2013;7:201.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ye X, Yan T, Chopp M, Zacharek A, Ning R, Venkat P, et al. Combination BMSC and Niaspan treatment of stroke enhances white matter remodeling and synaptic protein expression in diabetic rats. Int J Mol Sci. 2013;14(11):22221–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. van Velthoven CT, Dzietko M, Wendland MF, Derugin N, Faustino J, Heijnen CJ, et al. Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. J Neurosci Res. 2017;95(5):1225–36.

    Article  PubMed  CAS  Google Scholar 

  139. Maraka S, Jiang Q, Jafari-Khouzani K, Li L, Malik S, Hamidian H, et al. Degree of corticospinal tract damage correlates with motor function after stroke. Ann Clin Transl Neurol. 2014;1(11):891–9.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Zhu LL, Lindenberg R, Alexander MP, Schlaug G. Lesion load of the corticospinal tract predicts motor impairment in chronic stroke. Stroke. 2010;41(5):910–5.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Liu Z, Li Y, Qu R, Shen L, Gao Q, Zhang X, et al. Axonal sprouting into the denervated spinal cord and synaptic and postsynaptic protein expression in the spinal cord after transplantation of bone marrow stromal cell in stroke rats. Brain Res. 2007;1149:172–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Liu Z, Zhang RL, Li Y, Cui Y, Chopp M. Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. Stroke. 2009;40(7):2546–51.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Liu Z, Li Y, Zhang RL, Cui Y, Chopp M. Bone marrow stromal cells promote skilled motor recovery and enhance contralesional axonal connections after ischemic stroke in adult mice. Stroke. 2011;42(3):740–4.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Liu Z, Li Y, Zhang X, Savant-Bhonsale S, Chopp M. Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment. Stroke. 2008;39(9):2571–7.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, et al. Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab. 2004;24(4):441–8.

    Article  PubMed  Google Scholar 

  146. Xiong Y, Mahmood A, Chopp M. Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs. 2010;11(3):298–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Kojima T, Hirota Y, Ema M, Takahashi S, Miyoshi I, Okano H, et al. Subventricular zone-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells. 2010;28(3):545–54.

    PubMed  Google Scholar 

  148. Zhang RL, Zhang Z, Zhang L, Wang Y, Zhang C, Chopp M. Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res. 2006;83(7):1213–9.

    Article  CAS  PubMed  Google Scholar 

  149. Bao X, Wei J, Feng M, Lu S, Li G, Dou W, et al. Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. Brain Res. 2011;1367:103–13.

    Article  CAS  PubMed  Google Scholar 

  150. Chen J, Li Y, Zhang R, Katakowski M, Gautam SC, Xu Y, et al. Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. Brain Res. 2004;1005(1–2):21–8.

    Article  CAS  PubMed  Google Scholar 

  151. Zhang J, Li Y, Chen J, Yang M, Katakowski M, Lu M, et al. Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res. 2004;1030(1):19–27.

    Article  CAS  PubMed  Google Scholar 

  152. Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J, Teresa Vallejo-Cremades M, Fuentes B, Cerdan S, et al. Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther. 2013;4(1):11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. van Velthoven CT, Kavelaars A, Heijnen CJ. Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res. 2012;71(4 Pt 2):474–81.

    Article  PubMed  CAS  Google Scholar 

  154. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.

    Article  CAS  PubMed  Google Scholar 

  155. Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336–41.

    Article  CAS  PubMed  Google Scholar 

  156. Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:377.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22.

    Google Scholar 

  158. Otero-Ortega L, Gomez de Frutos MC, Laso-Garcia F, Rodriguez-Frutos B, Medina-Gutierrez E, Lopez JA, et al. Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2017:271678x17708917.

    Google Scholar 

  159. Xu JF, Yang GH, Pan XH, Zhang SJ, Zhao C, Qiu BS, et al. Altered microRNA expression profile in exosomes during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. PLoS One. 2014;9(12):e114627.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33(11):1711–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Xiong Y, Mahmood A, Chopp M. Emerging potential of exosomes for treatment of traumatic brain injury. Neural Regen Res. 2017;12(1):19–22.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Xiong Y, Zhang Y, Mahmood A, Chopp M. Investigational agents for treatment of traumatic brain injury. Expert Opin Investig Drugs. 2015;24(6):743–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zhang Y, Chopp M, Liu XS, Katakowski M, Wang X, Tian X, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol. 2017;54(4):2659–73.

    Article  CAS  PubMed  Google Scholar 

  166. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):1556–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhang ZG, Chopp M. Exosomes in stroke pathogenesis and therapy. J Clin Invest. 2016;126(4):1190–7.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Chopp M, Zhang ZG. Emerging potential of exosomes and noncoding microRNAs for the treatment of neurological injury/diseases. Expert Opin Emerg Drugs. 2015;20(4):523–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang ZG, Chopp M. Promoting brain remodeling to aid in stroke recovery. Trends Mol Med. 2015;21(9):543–8.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–5.

    Article  CAS  PubMed  Google Scholar 

  171. Sen CK. MicroRNAs as new maestro conducting the expanding symphony orchestra of regenerative and reparative medicine. Physiol Genomics. 2011;43(10):517–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Juranek JK, Geddis MS, Song F, Zhang J, Garcia J, Rosario R, et al. RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice. Diabetes. 2013;62(3):931–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Cui C, Ye X, Chopp M, Venkat P, Zacharek A, Yan T, et al. miR-145 regulates diabetes-bone marrow stromal cell-induced neurorestorative effects in diabetes stroke rats. Stem Cells Transl Med. 2016;

    Google Scholar 

  175. Wang XQ, Zhu XJ, Zou P. Research progress of mesenchymal stem cell-derived microvesicle. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013;21(1):227–30.

    CAS  PubMed  Google Scholar 

  176. Xin H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48(3):747–53.

    Article  CAS  PubMed  Google Scholar 

  177. Zhang Y, Ueno Y, Liu XS, Buller B, Wang X, Chopp M, et al. The MicroRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. J Neurosci. 2013;33(16):6885–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Xin H, Wang F, Li Y, Lu QE, Cheung WL, Zhang Y, et al. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant. 2017;26(2):243–57.

    Article  PubMed  Google Scholar 

  179. Wen Z, Zheng S, Zhou C, Yuan W, Wang J, Wang T. Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators. J Cell Mol Med. 2012;16(4):657–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI, 48202, USA

    Yi Shen M.D., Poornima Venkat Ph.D., Michael Chopp Ph.D. & Jieli Chen M.D.

  2. Gerontology & Neurological Institute, Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Yi Shen M.D. & Jieli Chen M.D.

  3. Department of Physics, Oakland University, Rochester, MI, 48309, USA

    Michael Chopp Ph.D.

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  1. Yi Shen M.D.
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  2. Poornima Venkat Ph.D.
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  3. Michael Chopp Ph.D.
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  4. Jieli Chen M.D.
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Correspondence to Michael Chopp Ph.D. or Jieli Chen M.D. .

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  1. Department of Neurology & Neurosurgery, Cedars-Sinai Medical Center, AHSP, Los Angeles, California, USA

    Paul A. Lapchak

  2. Department of Physiology, Loma Linda University, Loma Linda, California, USA

    John H. Zhang

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Shen, Y., Venkat, P., Chopp, M., Chen, J. (2018). Mesenchymal Stromal Cell Therapy of Stroke. In: Lapchak, P., Zhang, J. (eds) Cellular and Molecular Approaches to Regeneration and Repair. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-66679-2_11

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