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Bone Marrow Mesenchymal Stromal Cell Transplantation: A Neurorestorative Therapy for Stroke

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Cellular Therapy for Stroke and CNS Injuries

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

Abstract

A decade long focus on neuroprotection for stroke and neural injury, and its failure to translate into the clinical setting has led to a major shift of focus from neuroprotection to neurorestoration. Neurorestoration involves the remodeling and rekindling of neurovascular plasticity within the central nervous system which drive neurological recovery. Bone marrow-derived mesenchymal stem cell (BMSC) therapy is a promising cell-based neurorestorative therapy for stroke. This chapter provides an update on the use of BMSCs to promote neurorestorative effects in the sub-acute and chronic phases after stroke. The biological processes involved in promoting neurorestorative effects post ischemia are outlined, molecular mechanisms that promote neurogenesis, synaptogenesis, vascular and white matter remodeling, and neurovascular interactions and plasticity are discussed, the involvement of microRNA’s in regulating neurorestorative mechanisms is introduced, and an update on clinical trials for BMSC treatment of stroke is presented.

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Abbreviations

BMSCs :

Bone marrow-derived mesenchymal stem cells

miRNA :

microRNA

tPA :

Tissue plasminogen activator

MSCs :

Marrow stromal cells

BBB :

Brain-blood-barrier

NeuN :

Neuron-specific nuclear protein

GFP :

Green fluorescent protein

IBZ :

ischemic border zone

GFAP :

Glial fibrillary acidic protein

VEGF :

vascular endothelial growth factor

FGF2 :

Basic fibroblast growth factor

PGF :

Placental growth factor

IGF :

Insulin-like growth factor

BDNF :

Brain derived neurotrophic factor

HGF:

hepatocyte growth factor

Ang1 :

Angiopoietin-1

SVZ :

sub-ventricular zone

GDNF:

Glial cell-derived neurotrophic factor

NGF :

Nerve growth factor

SDF:

Stromal cell-derived factor 1

CBF :

Cerebral blood flow

PDGF :

Platelet derived growth factor

MMP :

Matrix metalloproteinase

OPC’s :

Oligodendrocyte progenitor cells

OLs :

Oligodendrocytes

T1DM :

Type-one diabetes mellitus

MCAo :

Middle cerebral artery occlusion

HBMSCs :

Human BMSCs

References

  • Andrews EM, Tsai SY, Johnson SC, Farrer JR, Wagner JP, Kopen GC, Kartje GL (2008) Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat. Exp Neurol 211:588–592

    CAS  PubMed Central  PubMed  Google Scholar 

  • Arenillas JF, Sobrino T, Castillo J, Davalos A (2007) The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med 9:205–212

    PubMed  Google Scholar 

  • Ay H, Ay I, Koroshetz WJ, Finklestein SP (1999) Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc Dis 9:131–135

    CAS  PubMed  Google Scholar 

  • Ay I, Sugimori H, Finklestein SP (2001) Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 87:71–80

    CAS  PubMed  Google Scholar 

  • Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, Arvin KL, Holtzman DM (2002) Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 22:455–463

    CAS  PubMed  Google Scholar 

  • Bang OY, Lee JS, Lee PH, Lee G (2005) Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57:874–882

    PubMed  Google Scholar 

  • Bao X, Wei J, Feng M, Lu S, Li G, Dou W, Ma W, Ma S, An Y, Qin C, Zhao RC, Wang R (2011) Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. Brain Res 7:103–113

    Google Scholar 

  • Buschmann I, Schaper W (2000) The pathophysiology of the collateral circulation (arteriogenesis). J Pathol 190:338–342

    CAS  PubMed  Google Scholar 

  • Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    CAS  PubMed  Google Scholar 

  • Chang SJ, Weng SL, Hsieh JY, Wang TY, Chang MD, Wang HW (2011) MicroRNA-34a modulates genes involved in cellular motility and oxidative phosphorylation in neural precursors derived from human umbilical cord mesenchymal stem cells. BMC Med Genomics 4:65

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M (2001a) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32:1005–1011

    CAS  PubMed  Google Scholar 

  • Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, Chopp M (2001b) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:2682–2688

    CAS  PubMed  Google Scholar 

  • Chen X, Katakowski M, Li Y, Lu D, Wang L, Zhang L, Chen J, Xu Y, Gautam S, Mahmood A, Chopp M (2002a) Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res 69:687–691

    CAS  PubMed  Google Scholar 

  • Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J, Xu Y, Gautam SC, Chopp M (2002b) Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology 22:275–279

    PubMed  Google Scholar 

  • Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003a) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778–786

    CAS  PubMed  Google Scholar 

  • Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M (2003b) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92:692–699

    CAS  PubMed  Google Scholar 

  • Chen J, Cui X, Zacharek A, Jiang H, Roberts C, Zhang C, Lu M, Kapke A, Feldkamp CS, Chopp M (2007) Niaspan increases angiogenesis and improves functional recovery after stroke. Ann Neurol 62:49–58

    CAS  PubMed  Google Scholar 

  • Chen JR, Cheng GY, Sheu CC, Tseng GF, Wang TJ, Huang YS (2008) Transplanted bone marrow stromal cells migrate, differentiate and improve motor function in rats with experimentally induced cerebral stroke. J Anat 213:249–258

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen J, Cui X, Zacharek A, Ding GL, Shehadah A, Jiang Q, Lu M, Chopp M (2009) Niaspan treatment increases tumor necrosis factor-alpha-converting enzyme and promotes arteriogenesis after stroke. J Cereb Blood Flow Metab 29:911–920

    PubMed Central  PubMed  Google Scholar 

  • Chen J, Cui X, Zacharek A, Cui Y, Roberts C, Chopp M (2011a) White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke 42:445–452

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen J, Ye X, Yan T, Zhang C, Yang XP, Cui X, Cui Y, Zacharek A, Roberts C, Liu X, Dai X, Lu M, Chopp M (2011b) Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke 42:3551–3558

    PubMed Central  PubMed  Google Scholar 

  • Collino F, Bruno S, Deregibus MC, Tetta C, Camussi G (2011) Chapter fourteen–microRNAs and mesenchymal stem cells. In: Gerald L (ed) Vitamins & hormones, vol 87. Academic, Massachusetts, pp 291–320

    Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cui X, Chopp M, Zacharek A, Roberts C, Buller B, Ion M, Chen J (2010) Niacin treatment of stroke increases synaptic plasticity and axon growth in rats. Stroke 41:2044–2049

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ding J, Cheng Y, Gao S, Chen J (2011) Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res 89:222–230

    CAS  PubMed  Google Scholar 

  • Ding X, Li Y, Liu Z, Zhang J, Cui Y, Chen X, Chopp M (2013) The sonic hedgehog pathway mediates brain plasticity and subsequent functional recovery after bone marrow stromal cell treatment of stroke in mice. J Cereb Blood Flow Metab 33:1015–1024

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    CAS  PubMed  Google Scholar 

  • Dor Y, Keshet E (1997) Ischemia-driven angiogenesis. Trends Cardiovasc Med 7:289–294

    CAS  PubMed  Google Scholar 

  • Duffy GP, Ahsan T, O’Brien T, Barry F, Nerem RM (2009) Bone marrow-derived mesenchymal stem cells promote angiogenic processes in a time- and dose-dependent manner in vitro. Tissue Eng Part A 15:2459–2470

    CAS  PubMed  Google Scholar 

  • Erdo F, Buschmann IR (2007) Arteriogenesis: a new strategy of therapeutic intervention in chronic arterial disorders. Cellular mechanism and experimental models. Orv Hetil 148:633–642

    PubMed  Google Scholar 

  • Feng Y, Wang Y, Pfister F, Hillebrands JL, Deutsch U, Hammes HP (2009) Decreased hypoxia-induced neovascularization in angiopoietin-2 heterozygous knockout mouse through reduced MMP activity. Cell Physiol Biochem 23:277–284

    CAS  PubMed  Google Scholar 

  • Folkman J, D’Amore PA (1996) Blood vessel formation: what is its molecular basis? Cell 87:1153–1155

    CAS  PubMed  Google Scholar 

  • Francis KR, Wei L (2010) Human embryonic stem cell neural differentiation and enhanced cell survival promoted by hypoxic preconditioning. Cell Death Dis 1:22

    Google Scholar 

  • Greenberg DA (1998) Angiogenesis and stroke. Drug News Perspect 11:265–270

    CAS  PubMed  Google Scholar 

  • Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J, Teresa Vallejo-Cremades M, Fuentes B, Cerdan S, Diez-Tejedor E (2013) 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 4:11

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hardy SA, Maltman DJ, Przyborski SA (2008) Mesenchymal stem cells as mediators of neural differentiation. Curr Stem Cell Res Ther 3:43–52

    CAS  PubMed  Google Scholar 

  • Hayase M, Kitada M, Wakao S, Itokazu Y, Nozaki K, Hashimoto N, Takagi Y, Dezawa M (2009) Committed neural progenitor cells derived from genetically modified bone marrow stromal cells ameliorate deficits in a rat model of stroke. J Cereb Blood Flow Metab 29:1409–1420

    CAS  PubMed  Google Scholar 

  • Hayashi T, Abe K, Itoyama Y (1998) Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab 18:887–895

    CAS  PubMed  Google Scholar 

  • Hoffmann J, Glassford AJ, Doyle TC, Robbins RC, Schrepfer S, Pelletier MP (2010) Angiogenic effects despite limited cell survival of bone marrow-derived mesenchymal stem cells under ischemia. Thorac Cardiovasc Surg 58:136–142

    CAS  PubMed  Google Scholar 

  • Huang F, Zhu X, Hu XQ, Fang ZF, Tang L, Lu XL, Zhou SH (2013) Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate Notch ligand Delta-like-4, enhancing ischemic angiogenesis and cell survival. Int J Mol Med 31:484–492

    CAS  PubMed  Google Scholar 

  • Juranek JK, Geddis MS, Song F, Zhang J, Garcia J, Rosario R, Yan SF, Brannagan TH, Schmidt AM (2013) RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice. Diabetes 62:931–943

    CAS  PubMed Central  PubMed  Google Scholar 

  • Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, Shu W, Jiang F, Chopp M (2013) Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 335:201–204

    CAS  PubMed Central  PubMed  Google Scholar 

  • Katsuda T, Kosaka N, Takeshita F, Ochiya T (2013) The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics 13:1637–1653

    CAS  PubMed  Google Scholar 

  • Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE (2004) 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 94:678–685

    CAS  PubMed  Google Scholar 

  • Kobayashi T, Ahlenius H, Thored P, Kobayashi R, Kokaia Z, Lindvall O (2006) Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats. Stroke 37:2361–2367

    CAS  PubMed  Google Scholar 

  • Krebsbach PH, Kuznetsov SA, Bianco P, Robey PG (1999) Bone marrow stromal cells: characterization and clinical application. Crit Rev Oral Biol Med 10:165–181

    CAS  PubMed  Google Scholar 

  • Laine SK, Alm JJ, Virtanen SP, Aro HT, Laitala-Leinonen TK (2012) MicroRNAs miR-96, miR-124, and miR-199a regulate gene expression in human bone marrow-derived mesenchymal stem cells. J Cell Biochem 113:2687–2695

    CAS  PubMed  Google Scholar 

  • Lee TH, Kato H, Chen ST, Kogure K, Itoyama Y (1998) Expression of nerve growth factor and trkA after transient focal cerebral ischemia in rats. Stroke 29:1687–1696

    CAS  PubMed  Google Scholar 

  • Lee J, Kuroda S, Shichinohe H, Ikeda J, Seki T, Hida K, Tada M, Sawada K, Iwasaki Y (2003) Migration and differentiation of nuclear fluorescence-labeled bone marrow stromal cells after transplantation into cerebral infarct and spinal cord injury in mice. Neuropathology 23:169–180

    PubMed  Google Scholar 

  • Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY (2010) A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28:1099–1106

    PubMed  Google Scholar 

  • Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514–523

    CAS  PubMed  Google Scholar 

  • Li Y, McIntosh K, Chen J, Zhang C, Gao Q, Borneman J, Raginski K, Mitchell J, Shen L, Zhang J, Lu D, Chopp M (2006) Allogeneic bone marrow stromal cells promote glial-axonal remodeling without immunologic sensitization after stroke in rats. Exp Neurol 198:313–325

    CAS  PubMed  Google Scholar 

  • Li WY, Choi YJ, Lee PH, Huh K, Kang YM, Kim HS, Ahn YH, Lee G, Bang OY (2008) Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. Cell Transplant 17:1045–1059

    PubMed  Google Scholar 

  • Lim PK, Patel SA, Gregory LA, Rameshwar P (2010) Neurogenesis: role for microRNAs and mesenchymal stem cells in pathological states. Curr Med Chem 17:2159–2167

    CAS  PubMed  Google Scholar 

  • Liu Z, Li Y, Zhang X, Savant-Bhonsale S, Chopp M (2008) Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment. Stroke 39:2571–2577

    PubMed Central  PubMed  Google Scholar 

  • Liu Z, Zhang RL, Li Y, Cui Y, Chopp M (2009) Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. Stroke 40:2546–2551

    PubMed Central  PubMed  Google Scholar 

  • Liu Z, Li Y, Zhang ZG, Cui X, Cui Y, Lu M, Savant-Bhonsale S, Chopp M (2010) Bone marrow stromal cells enhance inter- and intracortical axonal connections after ischemic stroke in adult rats. J Cereb Blood Flow Metab 30:1288–1295

    PubMed Central  PubMed  Google Scholar 

  • Liu X, Ye R, Yan T, Yu SP, Wei L, Xu G, Fan X, Jiang Y, Stetler RA, Liu G, Chen J (2014) Cell based therapies for ischemic stroke: from basic science to bedside. Prog Neurobiol 115C:92–115

    Google Scholar 

  • Malgieri A, Kantzari E, Patrizi MP, Gambardella S (2010) Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med 3:248–269

    PubMed Central  PubMed  Google Scholar 

  • Moniche F, Gonzalez A, Gonzalez-Marcos JR, Carmona M, Pinero P, Espigado I, Garcia-Solis D, Cayuela A, Montaner J, Boada C, Rosell A, Jimenez MD, Mayol A, Gil-Peralta A (2012) Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke 43:2242–2244

    PubMed  Google Scholar 

  • Navarro-Sobrino M, Rosell A, Hernandez-Guillamon M, Penalba A, Boada C, Domingues-Montanari S, Ribo M, Alvarez-Sabin J, Montaner J (2011) A large screening of angiogenesis biomarkers and their association with neurological outcome after ischemic stroke. Atherosclerosis 216:205–211

    CAS  PubMed  Google Scholar 

  • Nikolic I, Plate KH, Schmidt MH (2010) EGFL7 meets miRNA-126: an angiogenesis alliance. J Angiogene Res 2:9

    Google Scholar 

  • Ohab JJ, Fleming S, Blesch A, Carmichael ST (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016

    CAS  PubMed  Google Scholar 

  • Papadopoulos CM, Tsai SY, Cheatwood JL, Bollnow MR, Kolb BE, Schwab ME, Kartje GL (2006) Dendritic plasticity in the adult rat following middle cerebral artery occlusion and Nogo-A neutralization. Cereb Cortex 16:529–536

    PubMed  Google Scholar 

  • Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813

    PubMed  Google Scholar 

  • Pham LD, Hayakawa K, Seo JH, Nguyen MN, Som AT, Lee BJ, Guo S, Kim KW, Lo EH, Arai K (2012) Crosstalk between oligodendrocytes and cerebral endothelium contributes to vascular remodeling after white matter injury. Glia 60:875–881

    PubMed Central  PubMed  Google Scholar 

  • Pirzad Jahromi G, Seidi S, Sadr SS, Shabanzadeh AP, Keshavarz M, Kaka GR, Hosseini SK, Sohanaki H, Charish J (2012) Therapeutic effects of a combinatorial treatment of simvastatin and bone marrow stromal cells on experimental embolic stroke. Basic Clin Pharmacol Toxicol 110:487–493

    CAS  PubMed  Google Scholar 

  • Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320

    CAS  PubMed  Google Scholar 

  • Ploughman M, Windle V, MacLellan CL, White N, Dore JJ, Corbett D (2009) Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke 40:1490–1495

    CAS  PubMed  Google Scholar 

  • Pratt PF, Medhora M, Harder DR (2004) Mechanisms regulating cerebral blood flow as therapeutic targets. Curr Opin Investig Drugs 5:952–956

    CAS  PubMed  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    CAS  PubMed  Google Scholar 

  • Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247–256

    CAS  PubMed  Google Scholar 

  • Schaper W, Buschmann I (1999) Arteriogenesis, the good and bad of it. Eur Heart J 20:1297–1299

    CAS  PubMed  Google Scholar 

  • Scholz D, Cai WJ, Schaper W (2001) Arteriogenesis, a new concept of vascular adaptation in occlusive disease. Angiogenesis 4:247–257

    CAS  PubMed  Google Scholar 

  • Sen CK (2011) MicroRNAs as new maestro conducting the expanding symphony orchestra of regenerative and reparative medicine. Physiol Genomics 43:517–520

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shehadah A, Chen J, Zacharek A, Cui Y, Ion M, Roberts C, Kapke A, Chopp M (2010) Niaspan treatment induces neuroprotection after stroke. Neurobiol Dis 40:277–283

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shen LH, Li Y, Chen J, Zhang J, Vanguri P, Borneman J, Chopp M (2006) Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience 137:393–399

    CAS  PubMed  Google Scholar 

  • Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (2007) Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6–13

    PubMed  Google Scholar 

  • Shen LH, Xin H, Li Y, Zhang RL, Cui Y, Zhang L, Lu M, Zhang ZG, Chopp M (2011) Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice. Stroke 42:459–464

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shichinohe H, Kuroda S, Lee JB, Nishimura G, Yano S, Seki T, Ikeda J, Tamura M, Iwasaki Y (2004) In vivo tracking of bone marrow stromal cells transplanted into mice cerebral infarct by fluorescence optical imaging. Brain Res Brain Res Protoc 13:166–175

    PubMed  Google Scholar 

  • Shichinohe H, Kuroda S, Maruichi K, Osanai T, Sugiyama T, Chiba Y, Yamaguchi A, Iwasaki Y (2010) Bone marrow stromal cells and bone marrow-derived mononuclear cells: which are suitable as cell source of transplantation for mice infarct brain? Neuropathology 30:113–122

    PubMed  Google Scholar 

  • Sondell M, Lundborg G, Kanje M (1999) Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 19:5731–5740

    CAS  PubMed  Google Scholar 

  • Suarez-Monteagudo C, Hernandez-Ramirez P, Alvarez-Gonzalez L, Garcia-Maeso I, de la Cuetara-Bernal K, Castillo-Diaz L, Bringas-Vega ML, Martinez-Aching G, Morales-Chacon LM, Baez-Martin MM, Sanchez-Catasus C, Carballo-Barreda M, Rodriguez-Rojas R, Gomez-Fernandez L, Alberti-Amador E, Macias-Abraham C, Balea ED, Rosales LC, Del Valle Perez L, Ferrer BB, Gonzalez RM, Bergado JA (2009) Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci 27:151–161

    PubMed  Google Scholar 

  • Sykova E, Jendelova P, Urdzikova L, Lesny P, Hejcl A (2006) Bone marrow stem cells and polymer hydrogels-two strategies for spinal cord injury repair. Cell Mol Neurobiol 26:1113–1129

    CAS  PubMed  Google Scholar 

  • Theus MH, Wei L, Cui L, Francis K, Hu X, Keogh C, Yu SP (2008) 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 210:656–670

    CAS  PubMed  Google Scholar 

  • Tohill M, Mantovani C, Wiberg M, Terenghi G (2004) Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett 362:200–203

    CAS  PubMed  Google Scholar 

  • van Royen N, Piek JJ, Buschmann I, Hoefer I, Voskuil M, Schaper W (2001) Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease. Cardiovasc Res 49:543–553

    PubMed  Google Scholar 

  • van Velthoven CT, Kavelaars A, Heijnen CJ (2012) Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res 71:474–481

    PubMed  Google Scholar 

  • Wakabayashi K, Nagai A, Sheikh AM, Shiota Y, Narantuya D, Watanabe T, Masuda J, Kobayashi S, Kim SU, Yamaguchi S (2010) Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res 88:1017–1025

    CAS  PubMed  Google Scholar 

  • Walmsley AR, Mir AK (2007) Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. Curr Pharm Des 13:2470–2484

    CAS  PubMed  Google Scholar 

  • Wang XQ, Zhu XJ, Zou P (2013) Research progress of mesenchymal stem cell-derived microvesicle. Zhongguo Shi Yan Xue Ye Xue Za Zhi 21:227–230

    CAS  PubMed  Google Scholar 

  • Watt SM, Gullo F, van der Garde M, Markeson D, Camicia R, Khoo CP, Zwaginga JJ (2013) The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. Br Med Bull 108:25–53

    PubMed  Google Scholar 

  • Weaver JD, Stetten G, Littlefield JW (1991) Partial trisomies in two spontaneously arising long-lived human keratinocyte lines. In vitro Cell Dev Biol 27A:670–675

    CAS  PubMed  Google Scholar 

  • Wei L, Fraser JL, Lu ZY, Hu X, Yu SP (2012) Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 46:635–645

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wen Z, Zheng S, Zhou C, Yuan W, Wang J, Wang T (2012) Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators. J Cell Mol Med 16:657–671

    CAS  PubMed  Google Scholar 

  • Weng JS, Liu N, Du HW, Chen RH, Zhang YX, Wang JH, Huang HP (2008) 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 24:34–37

    CAS  PubMed  Google Scholar 

  • Wu J, Sun Z, Sun HS, Weisel RD, Keating A, Li ZH, Feng ZP, Li RK (2008) Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell Transplant 16:993–1005

    PubMed  Google Scholar 

  • Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–1564

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M (2013a) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33:1711–1715

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M (2013b) 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 31:2737–2746

    CAS  PubMed  Google Scholar 

  • Xu J, Wu W, Zhang L, Dorset-Martin W, Morris MW, Mitchell ME, Liechty KW (2012) The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment. Diabetes 61:2906–2912

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yan BB, Wang LL, Qiao JF, Peng HS, Cao JY, Li HL, Jin LH (2005) Study of mechanism of differentiation of bone stromal stem cells into neurons in vitro. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 21:301–304

    PubMed  Google Scholar 

  • Yan T, Chopp M, Ye X, Liu Z, Zacharek A, Cui Y, Roberts C, Buller B, Chen J (2012) Niaspan increases axonal remodeling after stroke in type 1 diabetes rats. Neurobiol Dis 46:157–164

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yan T, Ye X, Chopp M, Zacharek A, Ning R, Venkat P, Roberts C, Lu M, Chen J (2013) Niaspan attenuates the adverse effects of bone marrow stromal cell treatment of stroke in type one diabetic rats. PloS One 8:e81199

    PubMed Central  PubMed  Google Scholar 

  • Ye X, Yan T, Chopp M, Zacharek A, Ning R, Venkat P, Roberts C, Chen J (2013) Combination BMSC and Niaspan treatment of stroke enhances white matter remodeling and synaptic protein expression in diabetic rats. Int J Mol Sci 14:22221–22232

    PubMed Central  PubMed  Google Scholar 

  • Yoo SW, Kim SS, Lee SY, Lee HS, Kim HS, Lee YD, Suh-Kim H (2008) Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model. Exp Mol Med 40:387–397

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yuan M, Wen SJ, Yang CX, Pang YG, Gao XQ, Liu XQ, Huang L, Yuan QL (2013) Transplantation of neural stem cells overexpressing glial cell line-derived neurotrophic factor enhances Akt and Erk1/2 signaling and neurogenesis in rats after stroke. Chin Med J 126:1302–1309

    CAS  PubMed  Google Scholar 

  • Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, Feng Y, Gao Q, Chopp M (2007) Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab 27:1684–1691

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zacharek A, Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M (2010) Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke 41:524–530

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zhang C, Li Y, Chen J, Gao Q, Zacharek A, Kapke A, Chopp M (2006a) Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. Neuroscience 141:687–695

    CAS  PubMed  Google Scholar 

  • Zhang RL, Zhang ZG, Lu M, Wang Y, Yang JJ, Chopp M (2006b) Reduction of the cell cycle length by decreasing G1 phase and cell cycle reentry expand neuronal progenitor cells in the subventricular zone of adult rat after stroke. J Cereb Blood Flow Metab 26:857–863

    PubMed  Google Scholar 

  • Zhang J, Li Y, Zhang ZG, Lu M, Borneman J, Buller B, Savant-Bhonsale S, Elias SB, Chopp M (2009) Bone marrow stromal cells increase oligodendrogenesis after stroke. J Cereb Blood Flow Metab 29:1166–1174

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang JH, Badaut J, Tang J, Obenaus A, Hartman R, Pearce WJ (2012) The vascular neural network–a new paradigm in stroke pathophysiology. Nat Rev Neurol 8:711–716

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang R, Chopp M, Zhang ZG (2013) Oligodendrogenesis after cerebral ischemia. Front Cell Neurosci 29,7:201 (eCollection)

    Google Scholar 

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

    PubMed  Google Scholar 

  • Zhao Y, Lai W, Xu Y, Li L, Chen Z, Wu W (2013) Exogenous and endogenous therapeutic effects of combination Sodium Ferulate and bone marrow stromal cells (BMSCs) treatment enhance neurogenesis after rat focal cerebral ischemia. Metab Brain Dis 28:655–666

    CAS  PubMed  Google Scholar 

  • Zhu CJ, Dong JX, Li J, Zhang MJ, Wang LP, Luo L (2011) Preliminary study on the mechanism of acupoint injection of bone marrow mesenchymal stem cells in improving blood flow in the rat of hind limb ischemia. J Tradit Chin Med 31:241–245

    PubMed  Google Scholar 

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Acknowledgements

Research reported in this publication was supported by National Institute on Aging under award number RO1AG031811 (JC), RO1AG 037506 (MC) and R41NS080329 (JC), and National Institute of Neurological Disorders and Stroke (NINDS) under award number RO1NS083078 (JC)

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Authors and Affiliations

  1. Department of Neurology, Henry Ford Hospital, E&R Building, 3091, 48202, Detroit, MI, USA

    Jieli Chen MD, Poornima Venkat & Michael Chopp

  2. Department of Physics, Oakland University, Rochester, MI, USA

    Poornima Venkat & Michael Chopp

Authors
  1. Jieli Chen MD
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  2. Poornima Venkat
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  3. Michael Chopp
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Corresponding author

Correspondence to Jieli Chen MD .

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Editors and Affiliations

  1. Department of Neurosurgery, SUNY Upstate Medical College, Syracuse, New York, USA

    Li-Ru Zhao

  2. Loma Linda University School of Medicine Depts of Physiology, Loma Linda, California, USA

    John H. Zhang

Conclusions and Acknowledgements

Conclusions and Acknowledgements

The major physiological mechanisms for BMSC treatment induced neurorestoration post stroke, include angiogenesis, arteriogenesis, neurogenesis and white matter remodeling . BMSC therapy also induces the interaction and coupling between these various neurorestorative events. The role of microRNAs in modulating biological pathways is also of prime interest to understand mechanisms of neurorestorative effects and to improve BMSC therapies for stroke. An update on clinical trials for BMSC therapy has also been presented.

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Chen, J., Venkat, P., Chopp, M. (2015). Bone Marrow Mesenchymal Stromal Cell Transplantation: A Neurorestorative Therapy for Stroke. In: Zhao, LR., Zhang, J. (eds) Cellular Therapy for Stroke and CNS Injuries. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-11481-1_4

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  • DOI: https://doi.org/10.1007/978-3-319-11481-1_4

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