Opportunities and Challenges: Stem Cell‐Based Therapy for the Treatment of Ischemic Stroke

Stem cell‐based therapy for ischemic stroke has been widely explored in animal models and provides strong evidence of benefits. In this review, we summarize the types of stem cells, various delivery routes, and tracking tools for stem cell therapy of ischemic stroke. MSCs, EPCs, and NSCs are the most explored cell types for ischemic stroke treatment. Although the mechanisms of stem cell‐based therapies are not fully understood, the most possible functions of the transplanted cells are releasing growth factors and regulating microenvironment through paracrine mechanism. Clinical application of stem cell‐based therapy is still in its infancy. The next decade of stem cell research in stroke field needs to focus on combining different stem cells and different imaging modalities to fully explore the potential of this therapeutic avenue: from bench to bedside and vice versa.

[1]  S. Sakiyama-Elbert,et al.  Survival, Differentiation, and Migration of High-Purity Mouse Embryonic Stem Cell-derived Progenitor Motor Neurons in Fibrin Scaffolds after Sub-Acute Spinal Cord Injury. , 2014, Biomaterials science.

[2]  Nirmal Singh,et al.  Amniotic fluid derived stem cells ameliorate focal cerebral ischaemia-reperfusion injury induced behavioural deficits in mice , 2007, Behavioural Brain Research.

[3]  M. Chopp,et al.  Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic , 2009, The Lancet Neurology.

[4]  V. Jeevanantham,et al.  Adult Bone Marrow Cell Therapy Improves Survival and Induces Long-Term Improvement in Cardiac Parameters: A Systematic Review and Meta-Analysis , 2012, Circulation.

[5]  T. Wakabayashi,et al.  Stem cells from human exfoliated deciduous tooth-derived conditioned medium enhance recovery of focal cerebral ischemia in rats. , 2013, Tissue engineering. Part A.

[6]  A. Verma.  Persistent inflammation alters the function of the endogenous brain stem cell compartment , 2009 .

[7]  T. Benzing,et al.  Poor Cell Survival Limits the Beneficial Impact of Mesenchymal Stem Cell Transplantation on Acute Kidney Injury , 2009, Nephron Experimental Nephrology.

[8]  Samia J. Khoury,et al.  Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R. Zhao,et al.  Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice. , 2007, Haematologica.

[10]  Hui Xu,et al.  Microfl uidic Investigation of BDNF-Enhanced Neural Stem Cell Chemotaxis in CXCL 12 Gradients , 2013 .

[11]  Jayakumar Rajadas,et al.  Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. , 2012, Biomaterials.

[12]  M. Shoichet,et al.  Creating permissive microenvironments for stem cell transplantation into the central nervous system. , 2012, Trends in biotechnology.

[13]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[14]  Yaojiong Wu,et al.  Three-dimensional spheroid-cultured mesenchymal stem cells devoid of embolism attenuate brain stroke injury after intra-arterial injection. , 2014, Stem cells and development.

[15]  R. Malenka,et al.  Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  Jae Min Lim,et al.  Improvement of Postnatal Neovascularization by Human Embryonic Stem Cell–Derived Endothelial-Like Cell Transplantation in a Mouse Model of Hindlimb Ischemia , 2007, Circulation.

[17]  D. Hicklin,et al.  Granulocyte colony‐stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  P. Chowienczyk,et al.  Progenitors in motion: mechanisms of mobilization of endothelial progenitor cells. , 2009, British journal of clinical pharmacology.

[19]  Ji-xian Wang,et al.  Silica-coated superparamagnetic iron oxide nanoparticles targeting of EPCs in ischemic brain injury. , 2013, Biomaterials.

[20]  J. Montaner,et al.  Factors Secreted by Endothelial Progenitor Cells Enhance Neurorepair Responses after Cerebral Ischemia in Mice , 2013, PloS one.

[21]  Joseph C. Wu,et al.  Long term non-invasive imaging of embryonic stem cells using reporter genes , 2009, Nature Protocols.

[22]  K. Houkin,et al.  Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia , 2009, Experimental Neurology.

[23]  Rongbiao Tang,et al.  Neurovascular Recovery via Cotransplanted Neural and Vascular Progenitors Leads to Improved Functional Restoration after Ischemic Stroke in Rats , 2014, Stem cell reports.

[24]  Ahmad Y. Sheikh,et al.  Comparison of Optical Bioluminescence Reporter Gene and Superparamagnetic Iron Oxide MR Contrast Agent as Cell Markers for Noninvasive Imaging of Cardiac Cell Transplantation , 2008, Molecular Imaging and Biology.

[25]  R. Guzman,et al.  Intra-Arterial Injection of Neural Stem Cells using a Microneedle Technique does not Cause Microembolic Strokes , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  Guo-Yuan Yang,et al.  Mesenchymal Stem Cells Maintain Blood‐Brain Barrier Integrity by Inhibiting Aquaporin‐4 Upregulation After Cerebral Ischemia , 2014, Stem cells.

[27]  N. Benvenisty,et al.  Clonal Analysis of Human Embryonic Stem Cell Differentiation into Teratomas , 2007, Stem cells.

[28]  D. Nam,et al.  Therapeutic effects of human adipose stem cell‐conditioned medium on stroke , 2012, Journal of neuroscience research.

[29]  Seung-Up Kim,et al.  Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. , 2008, Brain : a journal of neurology.

[30]  Yi Li,et al.  Intravenous Administration of Human Bone Marrow Stromal Cells Induces Angiogenesis in the Ischemic Boundary Zone After Stroke in Rats , 2003, Circulation research.

[31]  P. Lau,et al.  A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors , 2005, Glia.

[32]  R. Weissleder,et al.  Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging , 2002, European Radiology.

[33]  H. Naritomi,et al.  Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. , 2004, The Journal of clinical investigation.

[34]  A. Kavelaars,et al.  Nasal Administration of Stem Cells: A Promising Novel Route to Treat Neonatal Ischemic Brain Damage , 2010, Pediatric Research.

[35]  Oh Young Bang,et al.  Autologous mesenchymal stem cell transplantation in stroke patients , 2005, Annals of neurology.

[36]  B. Connor,et al.  Chemokines direct neural progenitor cell migration following striatal cell loss , 2009, Molecular and Cellular Neuroscience.

[37]  T. Shimazaki,et al.  Human neural stem/progenitor cells, expanded in long‐term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils , 2004, Journal of neuroscience research.

[38]  Joseph C. Wu,et al.  Comparison of Imaging Techniques for Tracking Cardiac Stem Cell Therapy , 2007, Journal of Nuclear Medicine.

[39]  O. Lindvall,et al.  Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. , 2013, Brain : a journal of neurology.

[40]  J. Grotta,et al.  Intravenous autologous bone marrow mononuclear cells for ischemic stroke , 2011, Annals of neurology.

[41]  Jun Yamashita,et al.  Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors , 2000, Nature.

[42]  Marcello Cadioli,et al.  Magnetic Resonance‐Based Tracking and Quantification of Intravenously Injected Neural Stem Cell Accumulation in the Brains of Mice with Experimental Multiple Sclerosis , 2007, Stem cells.

[43]  G. Martino,et al.  Neural stem/precursor cells for the treatment of ischemic stroke , 2008, Journal of Neurological Sciences.

[44]  I. Weissman,et al.  Functional and Transcriptional Characterization of Human Embryonic Stem Cell-Derived Endothelial Cells for Treatment of Myocardial Infarction , 2009, PloS one.

[45]  M. Lynch,et al.  Ischemic brain injury: a consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction. , 2013, Archives of biochemistry and biophysics.

[46]  K. Nozaki,et al.  Survival and differentiation of neural progenitor cells derived from embryonic stem cells and transplanted into ischemic brain. , 2005, Journal of neurosurgery.

[47]  Jian-min Li,et al.  Period2 Deficiency Blunts Hypoxia-Induced Mobilization and Function of Endothelial Progenitor Cells , 2014, PloS one.

[48]  N. Ikeda,et al.  VASCULAR ENDOTHELIAL GROWTH FACTOR GENE‐TRANSFERRED BONE MARROW STROMAL CELLS ENGINEERED WITH A HERPES SIMPLEX VIRUS TYPE 1 VECTOR CAN IMPROVE NEUROLOGICAL DEFICITS AND REDUCE INFARCTION VOLUME IN RAT BRAIN ISCHEMIA , 2007, Neurosurgery.

[49]  Rohan M. Modi,et al.  Heat Shock Improves Sca‐1+ Stem Cell Survival and Directs Ischemic Cardiomyocytes Toward a Prosurvival Phenotype Via Exosomal Transfer: A Critical Role for HSF1/miR‐34a/HSP70 Pathway , 2014, Stem cells.

[50]  S. W. Kim,et al.  MSC-based VEGF gene therapy in rat myocardial infarction model using facial amphipathic bile acid-conjugated polyethyleneimine. , 2014, Biomaterials.

[51]  Hsin-Yang Li,et al.  Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. , 2010, Stem cells and development.

[52]  W. Young,et al.  Endothelial progenitor cell transplantation improves long‐term stroke outcome in mice , 2010, Annals of neurology.

[53]  K. Abe,et al.  Tridermal Tumorigenesis of Induced Pluripotent Stem Cells Transplanted in Ischemic Brain , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[54]  K. Nozaki,et al.  Single and local blockade of interleukin‐6 signaling promotes neuronal differentiation from transplanted embryonic stem cell‐derived neural precursor cells , 2011, Journal of neuroscience research.

[55]  M. Chopp,et al.  Patterns and Dynamics of Subventricular Zone Neuroblast Migration in the Ischemic Striatum of the Adult Mouse , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[56]  R. Sacco,et al.  Efficacy and Dose-Dependent Safety of Intra-Arterial Delivery of Mesenchymal Stem Cells in a Rodent Stroke Model , 2014, PloS one.

[57]  Anne-Lise D. Maag,et al.  Adherent Self-Renewable Human Embryonic Stem Cell-Derived Neural Stem Cell Line: Functional Engraftment in Experimental Stroke Model , 2008, PloS one.

[58]  W. Frey,et al.  Intranasal delivery of cells to the brain. , 2009, European journal of cell biology.

[59]  Z. Han,et al.  Enhancement of neovascularization with cord blood CD133+ cell-derived endothelial progenitor cell transplantation , 2004, Thrombosis and Haemostasis.

[60]  Paul G Scott,et al.  Mesenchymal Stem Cells Enhance Wound Healing Through Differentiation and Angiogenesis , 2007, Stem cells.

[61]  J. S. Gutkind,et al.  Engineered Mesenchymal Stem Cells with Enhanced Tropism and Paracrine Secretion of Cytokines and Growth Factors to Treat Traumatic Brain Injury , 2015, Stem cells.

[62]  M. K. Kim,et al.  Human Neural Stem Cells Genetically Modified to Overexpress Akt1 Provide Neuroprotection and Functional Improvement in Mouse Stroke Model , 2009, PloS one.

[63]  Y. Huang,et al.  Endogenous Endothelial Progenitor Cells Participate in Neovascularization via CXCR4/SDF‐1 axis and Improve Outcome After Stroke , 2014, CNS neuroscience & therapeutics.

[64]  F. Prato,et al.  Determining the minimum number of detectable cardiac-transplanted 111In-tropolone-labelled bone-marrow-derived mesenchymal stem cells by SPECT , 2005, Physics in medicine and biology.

[65]  Timothy O'Brien,et al.  Superparamagnetic iron oxide nanoparticle targeting of MSCs in vascular injury. , 2013, Biomaterials.

[66]  H. Duan,et al.  Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton's Jelly mesenchymal stem cells after myocardial infarction. , 2012, Chinese medical journal.

[67]  S. Cramer,et al.  Evidence for High Translational Potential of Mesenchymal Stromal Cell Therapy to Improve Recovery from Ischemic Stroke , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[68]  A. Hirko,et al.  Modulation of Inflammatory Responses After Global Ischemia by Transplanted Umbilical Cord Matrix Stem Cells , 2008, Stem cells.

[69]  T. Iwama,et al.  The conditioned medium of murine and human adipose-derived stem cells exerts neuroprotective effects against experimental stroke model , 2012, Brain Research.

[70]  Jialin Zheng,et al.  CXCL12 Enhances Human Neural Progenitor Cell Survival Through a CXCR7‐ and CXCR4‐Mediated Endocytotic Signaling Pathway , 2012, Stem cells.

[71]  M. Chopp,et al.  Different routes of administration of human umbilical tissue-derived cells improve functional recovery in the rat after focal cerebral ischemia , 2012, Brain Research.

[72]  Emanuela Monni,et al.  Human‐Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke‐Damaged Brain , 2012, Stem cells.

[73]  Su-Chun Zhang,et al.  Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. , 2013, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[74]  K. Francis,et al.  In vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain , 2008, Experimental Neurology.

[75]  Lu Zhang,et al.  High MRI performance fluorescent mesoporous silica-coated magnetic nanoparticles for tracking neural progenitor cells in an ischemic mouse model. , 2013, Nanoscale.

[76]  M. Stuber,et al.  Magnetic Resonance Imaging Overestimates Ferumoxide-Labeled Stem Cell Survival After Transplantation in the Heart , 2008, Circulation.

[77]  Hong Xu,et al.  High MR sensitive fluorescent magnetite nanocluster for stem cell tracking in ischemic mouse brain. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[78]  S. Papson,et al.  “Model” , 1981 .

[79]  Z. Kokaia,et al.  Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke‐damaged rat striatum , 2007, The European journal of neuroscience.

[80]  K. Houkin,et al.  I.v. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat , 2005, Neuroscience.

[81]  Ji-xian Wang,et al.  Neural Stem Cell Protects Aged Rat Brain from Ischemia–Reperfusion Injury through Neurogenesis and Angiogenesis , 2014, Journal of Cerebral Blood Flow and Metabolism.

[82]  Malcolm K Horne,et al.  Three-dimensional nanofibrous scaffolds incorporating immobilized BDNF promote proliferation and differentiation of cortical neural stem cells. , 2010, Stem cells and development.

[83]  Robert A. Kloner,et al.  Systemic Delivery of Bone Marrow–Derived Mesenchymal Stem Cells to the Infarcted Myocardium: Feasibility, Cell Migration, and Body Distribution , 2003, Circulation.

[84]  H. Okano,et al.  Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum , 2006, The Journal of Neuroscience.

[85]  Takuya Matsunaga,et al.  Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. , 2011, Brain : a journal of neurology.

[86]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[87]  P. Stieg,et al.  Neurotransplantation of Fetal Porcine Cells in Patients with Basal Ganglia Infarcts: A Preliminary Safety and Feasibility Study , 2005, Cerebrovascular Diseases.

[88]  K. Jin,et al.  Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat , 2005, Neurobiology of Disease.

[89]  M. Chopp,et al.  Adult Bone Marrow Transplantation after Stroke in Adult Rats , 2001, Cell transplantation.

[90]  C. Murry,et al.  Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts. , 1999, Circulation.

[91]  Michel Modo,et al.  Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke , 2012, Stem cells.

[92]  K. Houkin,et al.  Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. , 2006, Brain : a journal of neurology.

[93]  A. Doi,et al.  Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction , 2010, Neuroscience Research.

[94]  Jian-xing Ma,et al.  PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway. , 2014, Investigative ophthalmology & visual science.

[95]  D. O’Toole,et al.  Mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein 27 expression. , 2013, Human gene therapy.

[96]  F. Prato,et al.  In Vivo SPECT Quantification of Transplanted Cell Survival After Engraftment Using 111In-Tropolone in Infarcted Canine Myocardium , 2009, Journal of Nuclear Medicine.

[97]  M. Weller,et al.  Multimodal Imaging of Neural Progenitor Cell Fate in Rodents , 2008, Molecular imaging.

[98]  T. Ma,et al.  Preconditioning Stem Cells for In Vivo Delivery , 2014, BioResearch open access.

[99]  C. Tung,et al.  Fluorescent peptide probes for in vivo diagnostic imaging , 2004, Biopolymers.

[100]  R. Wahl,et al.  111In oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction , 2003, Nuclear medicine communications.

[101]  H. Hampel,et al.  IFATS Collection: The Conditioned Media of Adipose Stromal Cells Protect Against Hypoxia‐Ischemia‐Induced Brain Damage in Neonatal Rats , 2009, Stem cells.

[102]  M. Chopp,et al.  Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery , 2002, Neurology.

[103]  Satoshi Kuroda,et al.  Bone marrow stromal cells protect and repair damaged neurons through multiple mechanisms , 2008, Journal of neuroscience research.

[104]  R. Williams,et al.  The control of neuron number. , 1988, Annual review of neuroscience.

[105]  Gelin Xu,et al.  Intranasal delivery of stem cells to the brain , 2011, Expert opinion on drug delivery.

[106]  L. Tsai,et al.  Mesenchymal Stem Cells Primed With Valproate and Lithium Robustly Migrate to Infarcted Regions and Facilitate Recovery in a Stroke Model , 2011, Stroke.

[107]  J. Bulte,et al.  Cell Size and Velocity of Injection are Major Determinants of the Safety of Intracarotid Stem Cell Transplantation , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[108]  Lu Zhang,et al.  MRI/SPECT/Fluorescent Tri‐Modal Probe for Evaluating the Homing and Therapeutic Efficacy of Transplanted Mesenchymal Stem Cells in a Rat Ischemic Stroke Model , 2015, Advanced functional materials.

[109]  W. Xue,et al.  The Role of SDF-1-CXCR4/CXCR7 Axis in the Therapeutic Effects of Hypoxia-Preconditioned Mesenchymal Stem Cells for Renal Ischemia/Reperfusion Injury , 2012, PloS one.

[110]  S. Weiss,et al.  Erythropoietin Regulates the In Vitro and In Vivo Production of Neuronal Progenitors by Mammalian Forebrain Neural Stem Cells , 2001, The Journal of Neuroscience.

[111]  Ling Wei,et al.  Cell based therapies for ischemic stroke: From basic science to bedside , 2014, Progress in Neurobiology.

[112]  Ling Wei,et al.  Mobilization of Endogenous Bone Marrow Derived Endothelial Progenitor Cells and Therapeutic Potential of Parathyroid Hormone after Ischemic Stroke in Mice , 2014, PloS one.

[113]  A. Buchan,et al.  Transplantation of cultured human neuronal cells for patients with stroke , 2001, Neurology.

[114]  Brian A. Aguado,et al.  Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers. , 2012, Tissue engineering. Part A.

[115]  Martin G Pomper,et al.  Molecular neuroimaging: from conventional to emerging techniques. , 2007, Radiology.

[116]  H. Vliegen,et al.  Aortic root dysfunctioning and its effect on left ventricular function in Ross procedure patients assessed with magnetic resonance imaging. , 2006, American heart journal.

[117]  Hui Xu,et al.  Microfluidic investigation of BDNF-enhanced neural stem cell chemotaxis in CXCL12 gradients. , 2013, Small.

[118]  Q. Han,et al.  Transplantation of Flk‐1+ human bone marrow‐derived mesenchymal stem cells promotes angiogenesis and neurogenesis after cerebral ischemia in rats , 2011, The European journal of neuroscience.

[119]  A. Turnley,et al.  Systemically delivered Erythropoietin transiently enhances adult hippocampal neurogenesis , 2007, Journal of neurochemistry.

[120]  V. Feigin,et al.  Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010 , 2014, The Lancet.

[121]  S. Kumaran,et al.  Stem cell therapy: A clinical trial of stroke , 2013, Clinical Neurology and Neurosurgery.

[122]  S. Przyborski.  Differentiation of Human Embryonic Stem Cells After Transplantation in Immune‐Deficient Mice , 2005, Stem cells.

[123]  K. Houkin,et al.  Therapeutic Benefits by Human Mesenchymal Stem Cells (hMSCs) and Ang-1 Gene-Modified hMSCs after Cerebral Ischemia , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[124]  S. Williams,et al.  A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke , 2009, NeuroImage.

[125]  R. Weissleder,et al.  Bimodal Viral Vectors and In Vivo Imaging Reveal the Fate of Human Neural Stem Cells in Experimental Glioma Model , 2008, The Journal of Neuroscience.

[126]  R. Weissert,et al.  Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. , 2011, Rejuvenation research.

[127]  G. Comi,et al.  Human neural stem cells ameliorate autoimmune encephalomyelitis in non‐human primates , 2009, Annals of neurology.

[128]  Keiichi Magota,et al.  Bone Marrow Stromal Cell Transplantation Enhances Recovery of Local Glucose Metabolism After Cerebral Infarction in Rats: A Serial 18F-FDG PET Study , 2013, The Journal of Nuclear Medicine.

[129]  K. Satoh,et al.  Intra-arterial Cell Transplantation Provides Timing-Dependent Cell Distribution and Functional Recovery After Stroke , 2013, Stroke.

[130]  G. Martino,et al.  The therapeutic potential of neural stem cells , 2006, Nature Reviews Neuroscience.

[131]  V. Senyukov,et al.  Cell therapy of brain stroke , 2005, Bulletin of Experimental Biology and Medicine.

[132]  E. Brittebo,et al.  Intranasal delivery of central nervous system‐retargeted human mesenchymal stromal cells prolongs treatment efficacy of experimental autoimmune encephalomyelitis , 2014, Immunology.

[133]  I. Baumgartner,et al.  Novel Cell-Free Strategy for Therapeutic Angiogenesis: In Vitro Generated Conditioned Medium Can Replace Progenitor Cell Transplantation , 2009, PloS one.

[134]  Q. Dong,et al.  Induction of pluripotent stem cells transplantation therapy for ischemic stroke , 2011, Molecular and Cellular Biochemistry.

[135]  S. Yamaguchi,et al.  Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: Contribution of fractalkine and IL-5 , 2011, Neurobiology of Disease.

[136]  R. Guzman,et al.  BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery after Transplantation in Hypoxic–Ischemic Stroke , 2015, Cell transplantation.

[137]  K. Reymann,et al.  Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. , 2006, Brain : a journal of neurology.

[138]  G. Donnan,et al.  Neuroprotection: still achievable in humans. , 2008, Stroke.

[139]  Marta P Pereira,et al.  Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain , 2011, Brain : a journal of neurology.

[140]  Ling Wei,et al.  Delayed Intranasal Delivery of Hypoxic-Preconditioned Bone Marrow Mesenchymal Stem Cells Enhanced Cell Homing and Therapeutic Benefits after Ischemic Stroke in Mice , 2013, Cell transplantation.

[141]  Jurgen Seidel,et al.  Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. , 2009, Journal of the American College of Cardiology.

[142]  J. García-Verdugo,et al.  Persistent inflammation alters the function of the endogenous brain stem cell compartment , 2008, Brain : a journal of neurology.

[143]  Shinn-Zong Lin,et al.  Stem Cell Applications in Regenerative Medicine for Neurological Disorders , 2013, Cell transplantation.

[144]  Winfried Brenner,et al.  Assessment of the Tissue Distribution of Transplanted Human Endothelial Progenitor Cells by Radioactive Labeling , 2003, Circulation.

[145]  I. Weissman,et al.  Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[146]  K Walsh,et al.  Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. , 2001, Journal of molecular and cellular cardiology.

[147]  J. Shumsky,et al.  Treatments for , 2004 .

[148]  Ji-xian Wang,et al.  Effect of HMGB1 on the Paracrine Action of EPC Promotes Post‐Ischemic Neovascularization in Mice , 2014, Stem cells.

[149]  T. Biedermann,et al.  Intranasal Delivery of Bone Marrow-Derived Mesenchymal Stem Cells, Macrophages, and Microglia to the Brain in Mouse Models of Alzheimer's and Parkinson's Disease , 2014, Cell transplantation.

[150]  A. Ganser,et al.  Monitoring of Bone Marrow Cell Homing Into the Infarcted Human Myocardium , 2005, Circulation.

[151]  R. Wahl,et al.  Myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells , 2011, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[152]  H. Daldrup-Link,et al.  Labeling stem cells with fluorescent dyes for non-invasive detection with optical imaging. , 2008, Journal of visualized experiments : JoVE.

[153]  L. Dušek,et al.  Autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction: the effect of the dose of transplanted cells on myocardial function. , 2006, American heart journal.

[154]  K. Brunt,et al.  Ex Vivo Akt/HO-1 Gene Therapy to Human Endothelial Progenitor Cells Enhances Myocardial Infarction Recovery , 2012, Cell transplantation.

[155]  K. Jin,et al.  Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice , 2010, Proceedings of the National Academy of Sciences.

[156]  Sanjiv S. Gambhir,et al.  In Vivo Visualization of Embryonic Stem Cell Survival, Proliferation, and Migration After Cardiac Delivery , 2006, Circulation.

[157]  M. Chopp,et al.  Bone Marrow Stromal Cells Enhance Inter- and Intracortical Axonal Connections after Ischemic Stroke in Adult Rats , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[158]  Shinn-Zong Lin,et al.  Mouse-induced pluripotent stem cells generated under hypoxic conditions in the absence of viral infection and oncogenic factors and used for ischemic stroke therapy. , 2014, Stem cells and development.

[159]  Marcelo M. Cardoso,et al.  Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia , 2012, Neuroscience Research.

[160]  B. Cubelos,et al.  CXCR4/CXCR7 Molecular Involvement in Neuronal and Neural Progenitor Migration: Focus in CNS Repair , 2015, Journal of cellular physiology.

[161]  Wei Chen,et al.  MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4 , 2013, British Journal of Cancer.

[162]  Qihong Zhou,et al.  Effect of oxidative preconditioning on neural progenitor cells , 2008, Brain Research.

[163]  T. Palmer,et al.  The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain , 2011, Stroke.

[164]  F. Gavins,et al.  The potential of stem cell therapy for stroke: is PISCES the sign? , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[165]  P. Sanberg,et al.  Central Nervous System Entry of Peripherally Injected Umbilical Cord Blood Cells Is Not Required for Neuroprotection in Stroke , 2004, Stroke.

[166]  A. Zechariah,et al.  Transduction of Neural Precursor Cells with TAT‐Heat Shock Protein 70 Chaperone: Therapeutic Potential Against Ischemic Stroke after Intrastriatal and Systemic Transplantation , 2012, Stem cells.

[167]  P. Black,et al.  Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche , 2009, Brain Research.

[168]  G. Comi,et al.  Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. , 2009, Brain : a journal of neurology.

[169]  L. Ou,et al.  Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[170]  Ross Zafonte,et al.  Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. , 2005, Journal of neurosurgery.

[171]  Ling Wei,et al.  Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats , 2012, Neurobiology of Disease.

[172]  C. Case,et al.  Human Mesenchymal Stromal Cells and their Derivative, SB623 Cells, Rescue Neural Cells via Trophic Support following in Vitro Ischemia , 2010, Cell transplantation.

[173]  Amit N. Patel,et al.  Cell surface engineering to enhance mesenchymal stem cell migration toward an SDF-1 gradient. , 2014, Biomaterials.

[174]  Daniel T. Montoro,et al.  Enhancing stem cell survival in vivo for tissue repair. , 2013, Biotechnology advances.

[175]  Dong Ryul Lee,et al.  Therapeutic Potential of Human Induced Pluripotent Stem Cells in Experimental Stroke , 2013, Cell transplantation.

[176]  W. Xue,et al.  Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs. , 2010, Biochemical and biophysical research communications.

[177]  Seung U. Kim,et al.  Human Neural Stem Cells Over-Expressing VEGF Provide Neuroprotection, Angiogenesis and Functional Recovery in Mouse Stroke Model , 2007, PloS one.

[178]  S. Hendrix,et al.  Immunopharmacological intervention for successful neural stem cell therapy: New perspectives in CNS neurogenesis and repair. , 2014, Pharmacology & therapeutics.

[179]  T. Shimazaki,et al.  [Mammalian neural stem cells]. , 2008, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[180]  P. Walczak,et al.  Applicability and limitations of MR tracking of neural stem cells with asymmetric cell division and rapid turnover: The case of the Shiverer dysmyelinated mouse brain , 2007, Magnetic resonance in medicine.

[181]  O. Lindvall,et al.  Stem cells for the treatment of neurological disorders , 2006, Nature.

[182]  J. Kiss,et al.  VEGF is a chemoattractant for FGF-2–stimulated neural progenitors , 2003, The Journal of cell biology.

[183]  X. Niu,et al.  Human induced pluripotent stem cell-derived neural stem cells survive, migrate, differentiate, and improve neurologic function in a rat model of middle cerebral artery occlusion , 2013, Stem Cell Research & Therapy.