Classification and Characteristics of Mesenchymal Stem Cells and Its Potential Therapeutic Mechanisms and Applications against Ischemic Stroke

Ischemic stroke is a serious cerebral disease that often induces death and long-term disability. As a currently available therapy for recanalization after ischemic stroke, thrombolysis, including intravenous thrombolysis and endovascular therapy, still cannot be applicable to all patients due to the narrow time window. Mesenchymal stem cell (MSC) transplantation therapy, which can trigger neuronal regeneration and repair, has been considered as a significant advance in treatment of ischemic stroke. MSC transplantation therapy has exhibited its potential to improve the neurological function in ischemic stroke. Our review describes the current progress and future perspective of MSC transplantation therapy in ischemic stroke treatment, including cell types, transplantation approaches, therapeutic mechanisms, and preliminary clinical trials of MSC transplantation, for providing us an update role of MSC transplantation in ischemic stroke treatment.

[1]  Keke Zhang,et al.  Dental pulp stem cell‐derived exosomes alleviate cerebral ischaemia‐reperfusion injury through suppressing inflammatory response , 2021, Cell proliferation.

[2]  Yucong Peng,et al.  Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies , 2021, Frontiers in Cell and Developmental Biology.

[3]  Yun Chen,et al.  Comprehensive strategy of conduit guidance combined with VEGF producing Schwann cells accelerates peripheral nerve repair , 2021, Bioactive materials.

[4]  Chenchen Xie,et al.  Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis , 2021, Stem cell research & therapy.

[5]  Xiaokun Li,et al.  Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats , 2021, Bioactive materials.

[6]  Y. Kim,et al.  Efficacy and Safety of Intravenous Mesenchymal Stem Cells for Ischemic Stroke , 2021, Neurology.

[7]  S. Kuroda,et al.  Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke , 2020, International journal of molecular sciences.

[8]  A. Higuchi,et al.  Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries , 2020, Bioactive materials.

[9]  W. Powers Acute Ischemic Stroke. , 2020, The New England journal of medicine.

[10]  Chun Xu,et al.  Thermosensitive bFGF-Modified Hydrogel with Dental Pulp Stem Cells on Neuroinflammation of Spinal Cord Injury , 2020, ACS omega.

[11]  M. Hommel,et al.  Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial , 2020, Translational Stroke Research.

[12]  R. Lanza,et al.  Next-generation stem cells — ushering in a new era of cell-based therapies , 2020, Nature Reviews Drug Discovery.

[13]  T. Hyeon,et al.  Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke. , 2020, Biomaterials.

[14]  Michael S. Phipps,et al.  Management of acute ischemic stroke , 2020, BMJ.

[15]  D. Na,et al.  Intrathecal Injection in a Rat Model: A Potential Route to Deliver Human Wharton’s Jelly-Derived Mesenchymal Stem Cells into the Brain , 2020, International journal of molecular sciences.

[16]  Huanxiang Zhang,et al.  hUC-MSCs Exert a Neuroprotective Effect via Anti-apoptotic Mechanisms in a Neonatal HIE Rat Model , 2019, Cell transplantation.

[17]  S. Cramer,et al.  Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke. , 2019, Stroke.

[18]  Ling Gao,et al.  Tetramethylpyrazine attenuates blood-brain barrier disruption in ischemia/reperfusion injury through the JAK/STAT signaling pathway. , 2019, European journal of pharmacology.

[19]  I. Novak,et al.  Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic–Ischemic Brain Injury , 2019, International journal of molecular sciences.

[20]  Mingchang Li,et al.  Hippo/YAP signaling pathway mitigates blood-brain barrier disruption after cerebral ischemia/reperfusion injury , 2019, Behavioural Brain Research.

[21]  Mohammad Hossein Khosravi,et al.  Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017 , 2018, Lancet.

[22]  J. Cha,et al.  Application of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Stroke: Biodistribution and MicroRNA Study , 2018, Translational Stroke Research.

[23]  Huifang Xie,et al.  Autologous Endothelial Progenitor Cells Transplantation for Acute Ischemic Stroke: A 4‐Year Follow‐Up Study , 2018, Stem cells translational medicine.

[24]  Sai Zhang,et al.  Challenges and research progress of the use of mesenchymal stem cells in the treatment of ischemic stroke , 2018, Brain and Development.

[25]  Yanfeng Wu,et al.  Intrathecal Injection of Allogenic Bone Marrow-Derived Mesenchymal Stromal Cells in Treatment of Patients with Severe Ischemic Stroke: Study Protocol for a Randomized Controlled Observer-Blinded Trial , 2018, Translational Stroke Research.

[26]  S. Allan,et al.  The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke , 2018, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[27]  Guo-Yuan Yang,et al.  Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice , 2018, Journal of Neuroinflammation.

[28]  Lihua Luo,et al.  Effects of Transplanted Heparin-Poloxamer Hydrogel Combining Dental Pulp Stem Cells and bFGF on Spinal Cord Injury Repair , 2018, Stem cells international.

[29]  P. Hornsby,et al.  The Route by Which Intranasally Delivered Stem Cells Enter the Central Nervous System , 2018, Cell transplantation.

[30]  Yaoyao Geng,et al.  Differentiation of human dental pulp stem cells into neuronal by resveratrol , 2017, Cell biology international.

[31]  Y. Tabata,et al.  Peptide modified mesenchymal stem cells as targeting delivery system transfected with miR-133b for the treatment of cerebral ischemia. , 2017, International journal of pharmaceutics.

[32]  Ling Wei,et al.  Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke , 2017, Progress in Neurobiology.

[33]  Jae-Hyung Lee,et al.  Human Dental Pulp Stem Cells are more Effective than Human Bone Marrow-Derived Mesenchymal Stem Cells in Cerebral Ischemic Injury , 2017, Cell transplantation.

[34]  M. Chopp,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 , 2017, Cell transplantation.

[35]  M. Ameloot,et al.  Engineered neural tissue with Schwann cell differentiated human dental pulp stem cells: potential for peripheral nerve repair? , 2017, Journal of tissue engineering and regenerative medicine.

[36]  John H. Zhang,et al.  The High Cost of Stroke and Stroke Cytoprotection Research , 2016, Translational Stroke Research.

[37]  Qingwu Yang,et al.  GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats , 2016, Molecular Neurobiology.

[38]  Ling Wei,et al.  Long‐term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice , 2016, Brain pathology.

[39]  Carl A. Gregory,et al.  Mechanisms of mesenchymal stem/stromal cell function , 2016, Stem Cell Research & Therapy.

[40]  D. Petrović-Djergović,et al.  Inflammatory Disequilibrium in Stroke. , 2016, Circulation research.

[41]  Wutian Wu,et al.  An Overview of Protocols for the Neural Induction of Dental and Oral Stem Cells In Vitro. , 2016, Tissue engineering. Part B, Reviews.

[42]  A. David,et al.  Placental stem cells. , 2016, Best practice & research. Clinical obstetrics & gynaecology.

[43]  R. Keep,et al.  Translational Stroke Research on Blood-Brain Barrier Damage: Challenges, Perspectives, and Goals , 2016, Translational Stroke Research.

[44]  T. Asahara,et al.  Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair , 2016, Journal of the American Heart Association.

[45]  M. Farahmandnia,et al.  12 hours after cerebral ischemia is the optimal time for bone marrow mesenchymal stem cell transplantation , 2015, Neural regeneration research.

[46]  M. Gutiérrez-Fernández,et al.  Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke , 2015, Expert opinion on biological therapy.

[47]  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.

[48]  M. Moskowitz,et al.  Ischemic Stroke Activates Hematopoietic Bone Marrow Stem Cells , 2015, Circulation research.

[49]  Jie Pan,et al.  Human umbilical cord mesenchymal stem cells protect against ischemic brain injury in mouse by regulating peripheral immunoinflammation , 2015, Brain Research.

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

[51]  Mingfen Li,et al.  Mesenchymal stem cells suppress CD8+ T cell‐mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3‐dioxygenase and transforming growth factor‐β , 2014, Clinical and experimental immunology.

[52]  M. Gutiérrez-Fernández,et al.  Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. , 2014, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[53]  R. Dijkhuizen,et al.  Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury , 2014, Experimental Neurology.

[54]  Wei Cao,et al.  Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications , 2014, Nature Immunology.

[55]  A. Yoshimura,et al.  Post-ischemic inflammation regulates neural damage and protection , 2014, Front. Cell. Neurosci..

[56]  P. Gervois,et al.  Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. , 2014, Pharmacology & therapeutics.

[57]  Jia-sheng Fang,et al.  Comparison of administration routes for adipose-derived stem cells in the treatment of middle cerebral artery occlusion in rats. , 2014, Acta histochemica.

[58]  Jiaohong Wang,et al.  Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury , 2014, Hepatology.

[59]  P. Sanberg,et al.  Monocytes are essential for the neuroprotective effect of human cord blood cells following middle cerebral artery occlusion in rat , 2014, Molecular and Cellular Neuroscience.

[60]  M. Chopp,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 , 2013, Stem cells.

[61]  Andrew E Moran,et al.  Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010 , 2013, The Lancet. Global health.

[62]  L. Chamley,et al.  Human Placental Mesenchymal Stem Cells (pMSCs) Play a Role as Immune Suppressive Cells by Shifting Macrophage Differentiation from Inflammatory M1 to Anti-inflammatory M2 Macrophages , 2013, Stem Cell Reviews and Reports.

[63]  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.

[64]  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.

[65]  R. Sager,et al.  Stem Cells From Umbilical Cord Wharton’s Jelly From Preterm Birth Have Neuroglial Differentiation Potential , 2013, Reproductive Sciences.

[66]  M. Chopp,et al.  The sonic hedgehog pathway mediates brain plasticity and subsequent functional recovery after bone marrow stromal cell treatment of stroke in mice , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[67]  C. Case,et al.  Comparing the angiogenic potency of naïve marrow stromal cells and Notch-transfected marrow stromal cells , 2013, Journal of Translational Medicine.

[68]  I. Atsuta,et al.  Stem cells in dentistry--part I: stem cell sources. , 2012, Journal of prosthodontic research.

[69]  Jung Min Lee,et al.  Comparison of immunomodulatory effects of placenta mesenchymal stem cells with bone marrow and adipose mesenchymal stem cells. , 2012, International immunopharmacology.

[70]  J. Alder,et al.  Brain‐derived neurotrophic factor produced by human umbilical tissue‐derived cells is required for its effect on hippocampal dendritic differentiation , 2012, Developmental neurobiology.

[71]  M. Grãos,et al.  The secretome of stem cells isolated from the adipose tissue and Wharton jelly acts differently on central nervous system derived cell populations , 2012, Stem Cell Research & Therapy.

[72]  R. Vink,et al.  Human Adult Dental Pulp Stem Cells Enhance Poststroke Functional Recovery Through Non‐Neural Replacement Mechanisms , 2012, Stem cells translational medicine.

[73]  M. Ueda,et al.  Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. , 2011, The Journal of clinical investigation.

[74]  J. Chang,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 , 2011, Stem Cell Research & Therapy.

[75]  J. Y. Kim,et al.  Early Immunomodulation by Intravenously Transplanted Mesenchymal Stem Cells Promotes Functional Recovery in Spinal Cord Injured Rats. , 2011, Cell medicine.

[76]  Yu-Ching Lin,et al.  Human Umbilical Mesenchymal Stem Cells Promote Recovery After Ischemic Stroke , 2011, Stroke.

[77]  S. Gambhir,et al.  Biodistribution of Neural Stem Cells After Intravascular Therapy for Hypoxic–Ischemia , 2010, Stroke.

[78]  Shinil K. Shah,et al.  Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: Preserving the blood brain barrier via an interaction with splenocytes , 2010, Experimental Neurology.

[79]  R. Rosenwasser,et al.  Changes in Host Blood Factors and Brain Glia Accompanying the Functional Recovery after Systemic Administration of Bone Marrow Stem Cells in Ischemic Stroke Rats , 2010, Cell transplantation.

[80]  O. Bang,et al.  A Long‐Term Follow‐Up Study of Intravenous Autologous Mesenchymal Stem Cell Transplantation in Patients With Ischemic Stroke , 2010, Stem cells.

[81]  S. Fazel,et al.  Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: combined consequences for cell therapy in older recipients. , 2010, The Journal of thoracic and cardiovascular surgery.

[82]  Eric Farrell,et al.  The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. , 2010, Tissue engineering. Part B, Reviews.

[83]  K. Pennypacker,et al.  Human umbilical cord blood cell therapy blocks the morphological change and recruitment of CD11b‐expressing, isolectin‐binding proinflammatory cells after middle cerebral artery occlusion , 2009, Journal of neuroscience research.

[84]  A. Arthur,et al.  Implanted Adult Human Dental Pulp Stem Cells Induce Endogenous Axon Guidance , 2009, Stem cells.

[85]  Shinn-Zong Lin,et al.  MicroRNAs Regulation Modulated Self-Renewal and Lineage Differentiation of Stem Cells , 2009, Cell transplantation.

[86]  L. Moretta,et al.  MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. , 2009, Blood.

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

[88]  P. Dash,et al.  Intravenous mesenchymal stem cell therapy for traumatic brain injury. , 2009, Journal of neurosurgery.

[89]  Jeffrey M Karp,et al.  Mesenchymal stem cell homing: the devil is in the details. , 2009, Cell stem cell.

[90]  Ling Wei,et al.  Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice , 2008, Developmental neurobiology.

[91]  E. Gilerovich,et al.  Mesenchymal stem cells transplantation could be beneficial for treatment of experimental ischemic stroke in rats , 2008, Brain Research.

[92]  Brooke R. Snyder,et al.  Putative Dental Pulp‐Derived Stem/Stromal Cells Promote Proliferation and Differentiation of Endogenous Neural Cells in the Hippocampus of Mice , 2008, Stem cells.

[93]  E. Woods,et al.  Collection, cryopreservation, and characterization of human dental pulp-derived mesenchymal stem cells for banking and clinical use. , 2008, Tissue engineering. Part C, Methods.

[94]  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.

[95]  M. Chopp,et al.  Angiopoietin1/TIE2 and VEGF/FLK1 Induced by MSC Treatment Amplifies Angiogenesis and Vascular Stabilization after Stroke , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[96]  P. Hurn,et al.  Experimental Stroke Induces Massive, Rapid Activation of the Peripheral Immune System , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[97]  J. Shumsky,et al.  Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation. , 2006, Journal of neurotrauma.

[98]  A. Carrière,et al.  Plasticity of adipose tissue: a promising therapeutic avenue in the treatment of cardiovascular and blood diseases? , 2005, Archives des maladies du coeur et des vaisseaux.

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

[100]  E. Lam,et al.  Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. , 2005, Blood.

[101]  Yi Li,et al.  Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells , 2005, Glia.

[102]  Chun-Chieh Huang,et al.  Mesenchymal Stem Cells in the Wharton's Jelly of the Human Umbilical Cord , 2004, Stem cells.

[103]  Scott E. Fraser,et al.  Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study , 2004, NeuroImage.

[104]  Y. Romanov,et al.  Searching for Alternative Sources of Postnatal Human Mesenchymal Stem Cells: Candidate MSC‐Like Cells from Umbilical Cord , 2003, Stem cells.

[105]  Yi Li,et al.  Ischemic rat brain extracts induce human marrow stromal cell growth factor production , 2002, Neuropathology : official journal of the Japanese Society of Neuropathology.

[106]  R. P. Stroemer,et al.  Effects of Implantation Site of Stem Cell Grafts on Behavioral Recovery From Stroke Damage , 2002, Stroke.

[107]  G. W. Huntley,et al.  Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient mice delays the onset of neurological abnormalities and extends their life span. , 2002, The Journal of clinical investigation.

[108]  Michael Chopp,et al.  Bone Marrow-Derived Endothelial Progenitor Cells Participate in Cerebral Neovascularization After Focal Cerebral Ischemia in the Adult Mouse , 2002, Circulation research.

[109]  D. Corbett,et al.  A serial MR study of cerebral blood flow changes and lesion development following endothelin‐1‐induced ischemia in rats , 2001, Magnetic resonance in medicine.

[110]  S. Gronthos,et al.  Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[111]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[112]  N. Kulagina,et al.  Fibroblast precursors in normal and irradiated mouse hematopoietic organs. , 1976, Experimental hematology.

[113]  A. Arsenijević,et al.  Molecular Mechanisms Responsible for Anti-inflammatory and Immunosuppressive Effects of Mesenchymal Stem Cell-Derived Factors. , 2019, Advances in experimental medicine and biology.

[114]  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.

[115]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.