Skip to main content

Advertisement

SpringerLink
Log in

Neuroprotection of Stem Cells Against Ischemic Brain Injury: From Bench to Clinic

  • Review
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Neurological injuries can have numerous debilitating effects on functional status including sensorimotor deficits, cognitive impairment, and behavioral symptoms. Despite the disease burden, treatment options remain limited. Current pharmacological interventions are targeted at symptom management but are ineffective in reversing ischemic brain damage. Stem cell therapy for ischemic brain injury has shown promising preclinical and clinical results and has attracted attention as a potential therapeutic option. Various stem cell sources (embryonic, mesenchymal/bone marrow, and neural stem cells) have been investigated. This review provides an overview of the advances made in our understanding of the various types of stem cells and progress made in the use of these stem cells for the treatment of ischemic brain injuries. In particular, the use of stem cell therapy in global cerebral ischemia following cardiac arrest and in focal cerebral ischemia after ischemic stroke are discussed. The proposed mechanisms of stem cells’ neuroprotective effects in animal models (rat/mice, pig/swine) and other clinical studies, different routes of administration (intravenous/intra-arterial/intracerebroventricular/intranasal/intraperitoneal/intracranial) and stem cell preconditioning are discussed. Much of the promising data on stem cell therapies after ischemic brain injury remains in the experimental stage and several limitations remain unsettled. Future investigation is needed to further assess the safety and efficacy and to overcome the remaining obstacles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

N/A.

Abbreviations

AD-MSCs :

adipose-derived mesenchymal stem cells

BBB :

blood-brain barrier

BDNF :

brain-derived neurotrophic factor

BM-MNC :

bone marrow mononuclear cell

BM-MSCs :

bone marrow mesenchymal stem cells

CA :

cardiac arrest

CNS :

central nervous system

CPR :

cardiopulmonary resuscitation

CSF :

cerebral spinal liquid

DG :

dentate gyrus

EEG-IQ :

electroencephalogram information quantity

ESCs :

embryonic stem cells

ESC-NSCs :

embryonic stem cell-derived neural stem cells

ESC-NPCs :

embryonic stem cell-derived neural progenitor cells

EPs :

episomal plasmids

EVs :

extracellular vesicles

GDNF :

glial-derived neurotrophic factor

hASCs :

human adipose stem cells

hCNS-SCs :

human central nervous system stem cells

hNSCs :

human neural stem cells

HUCBCs :

human umbilical cord blood cells

IA :

intra-artery

IC :

intracranial

ICV :

intracerebroventricular

IP :

intraperitoneal

IV :

intravenous

iPSCs :

induced pluripotent stem cells

iPSC-MSCs :

induced pluripotent stem cell-derived mesenchymal stem cells

iPSC-NSCs :

induced pluripotent stem cell-derived - neural stem cell

IGF-1 :

insulin growth factor-1

MCAO :

middle cerebral arterial occlusion

MGE :

metabolic glycoengineering

MPC :

multipotent progenitor cell

MSCs :

mesenchymal stem cells

NDS :

neurological deficit score

NGF :

nerve growth factor

NPCs :

neural progenitor cells

NSCs :

neural stem cells

OEC :

olfactory ensheathing cell

OGD :

oxygen and glucose deprivation

PBS :

phosphate buffer solution

RCT :

randomized controlled trials

ROSC :

return of spontaneous circulation

RIP1 :

receptor-interacting protein kinase 1

SCs :

schwann cells

SVZ :

subventricular zone

TSP-1 :

thrombospondins 1

UCB :

umbilical cord blood

UCMSC :

umbilical cord mesenchymal stem cell

VEGF :

vascular endothelial growth factor

VF :

ventricular fibrillation

References

  1. Barthels D, Das H. Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol basis Dis. 2020;1866(4):165260.

    Article  CAS  PubMed  Google Scholar 

  2. Janardhan V, Qureshi AI. Mechanisms of ischemic brain injury. Curr Cardiol Rep. 2004;6(2):117–23.

    Article  PubMed  Google Scholar 

  3. Perkins GD, et al. Brain injury after cardiac arrest. Lancet. 2021;398(10307):1269–78.

    Article  PubMed  Google Scholar 

  4. Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med. 2021;47(12):1393–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ovbiagele B, Nguyen-Huynh MN. Stroke epidemiology: advancing our understanding of disease mechanism and therapy. Neurotherapeutics. 2011;8(3):319–29.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Javidi E, Magnus T. Autoimmunity After Ischemic Stroke and Brain Injury. Front Immunol. 2019;10:686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Orellana-Urzúa S, et al. Pathophysiology of ischemic stroke: role of oxidative stress. Curr Pharm Des. 2020;26(34):4246–60.

    Article  PubMed  Google Scholar 

  8. Wang Z, et al. Intracerebroventricular administration of hNSCs improves neurological recovery after cardiac arrest in rats. Stem Cell Rev Rep. 2021;17(3):923–37.

    Article  CAS  PubMed  Google Scholar 

  9. Wang Z, et al. Intracerebroventricular Administration of neural stem cells after cardiac arrest. Annu Int Conf IEEE Eng Med Biol Soc. 2019;2019:4213–6.

    PubMed  Google Scholar 

  10. Du J, et al. Glycoengineering human neural and adipose stem cells with novel thiol-modified n-acetylmannosamine (ManNAc) analogs. Cells. 2021;10(2):377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jia X, et al. 14: Boosting stem cell therapy by metabolic glycoengineering to improve outcomes after cardiac arrest. Crit Care Med. 2022;50(1):7.

    Article  Google Scholar 

  12. Wang Z, et al. Neuroprotection of NSC therapy is superior to glibenclamide in cardiac arrest-induced brain injury via neuroinflammation regulation. Transl Stroke Res. 2022:1–17.

  13. Zhang S, et al. Optimizing stem cell therapy after ischemic brain injury. J Stroke. 2020;22(3):286.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Maltman DJ, Hardy SA, Przyborski SA. Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem Int. 2011;59(3):347–56.

    CAS  PubMed  Google Scholar 

  15. Lennington JB, Yang Z, Conover JC. Neural stem cells and the regulation of adult neurogenesis. Reprod Biol Endocrinol. 2003;1(1):1–7.

    Article  Google Scholar 

  16. Kurozumi K, et al. Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther. 2005;11(1):96–104.

    Article  CAS  PubMed  Google Scholar 

  17. Yang Y, et al. Transfer of mitochondria from mesenchymal stem cells derived from induced pluripotent stem cells attenuates hypoxia-ischemia-induced mitochondrial dysfunction in PC12 cells. Neural Regen Res. 2020;15(3):464–72.

    Article  CAS  PubMed  Google Scholar 

  18. Liu K, et al. Mesenchymal stem cells transfer mitochondria into cerebral microvasculature and promote recovery from ischemic stroke. Microvasc Res. 2019;123:74–80.

    Article  CAS  PubMed  Google Scholar 

  19. Doberstein CA, et al. Current strategies in the surgical management of ischemic stroke. R I Med J. 2017;100(6):25.

    Google Scholar 

  20. Mahla RS. Stem cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol. 2016;2016:6940283.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen J, et al. 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 

  22. Wang F, et al. Transplanting mesenchymal stem cells for treatment of ischemic stroke. Cell Transplant. 2018;27(12):1825–34.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Iihoshi S, et al. A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats. Brain Res. 2004;1007(1-2):1–9.

    Article  CAS  PubMed  Google Scholar 

  24. Ishibashi S, et al. Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils. 2004;78(2):215–23.

  25. Stone LLH, et al. Amelioration of ischemic brain injury in rats with human umbilical cord blood stem cells: mechanisms of action. Cell Transplant. 2016;25(8):1473–88.

    Article  Google Scholar 

  26. Chen L, et al. Clinical efficacy and meta-analysis of stem cell therapies for patients with brain ischemia. 2016;2016:6129579.

  27. Detante O, et al. Controlled clinical trials of cell therapy in stroke: meta-analysis at six months after treatment. Int J Stroke. 2017;12(7):748–51.

    Article  PubMed  Google Scholar 

  28. Lees JS, et al. Stem cell-based therapy for experimental stroke: a systematic review and meta-analysis. Int J Stroke. 2012;7(7):582–8.

    Article  PubMed  Google Scholar 

  29. Rayasam A, et al. Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures? Immunology. 2018;154(3):363–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ding H, et al. Transplantation of placenta-derived mesenchymal stem cells reduces hypoxic-ischemic brain damage in rats by ameliorating the inflammatory response. Cell Mol Immunol. 2017;14(8):693–701.

    Article  CAS  PubMed  Google Scholar 

  31. Huang L, et al. Human neural stem cells rapidly ameliorate symptomatic inflammation in early-stage ischemic-reperfusion cerebral injury. Stem Cell Res Ther. 2014;5(6):1–16.

    Article  Google Scholar 

  32. Cheng Y, et al. Intravenously delivered neural stem cells migrate into ischemic brain, differentiate and improve functional recovery after transient ischemic stroke in adult rats. Int J Clin Exp Pathol. 2015;8(3):2928.

    PubMed  PubMed Central  Google Scholar 

  33. Gutiérrez-Fernández M, 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):1–12.

    Article  Google Scholar 

  34. Fischer UM, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–92.

    Article  CAS  PubMed  Google Scholar 

  35. Jung JW, et al. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J. 2013;54(5):1293–6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther. 2016;7(1):1–12.

    Article  Google Scholar 

  37. Cui LL, et al. The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity. Stem Cell Res Ther. 2015;6(1):1–9.

    Article  CAS  Google Scholar 

  38. Argibay B, et al. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci Rep. 2017;7(1):1–17.

    Article  Google Scholar 

  39. Cruz-Martinez P, et al. Intraventricular injections of mesenchymal stem cells activate endogenous functional remyelination in a chronic demyelinating murine model. 2016;7(5):e2223–3.

  40. Cheng Z, et al. Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice. J Neuroinflammation. 2018;15(1):1–11.

    Article  Google Scholar 

  41. Cunningham MG, et al. Preclinical evaluation of a novel intracerebral microinjection instrument permitting electrophysiologically guided delivery of therapeutics. Neurosurgery. 2004;54(6):1497–507.

    Article  PubMed  Google Scholar 

  42. Bazhanov N, et al. Intraperitoneally infused human mesenchymal stem cells form aggregates with mouse immune cells and attach to peritoneal organs. Stem Cell Res Ther. 2016;7(1):1–14.

    Article  Google Scholar 

  43. Chau MJ, et al. Delayed and repeated intranasal delivery of bone marrow stromal cells increases regeneration and functional recovery after ischemic stroke in mice. BMC Neurosci. 2018;19(1):1–12.

    Article  Google Scholar 

  44. Balyasnikova IV, et al. Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors. Mol Ther. 2014;22(1):140–8.

    Article  CAS  PubMed  Google Scholar 

  45. Dey M, et al. Intranasal oncolytic virotherapy with CXCR4-enhanced stem cells extends survival in mouse model of glioma. Stem Cell Rep. 2016;7(3):471–82.

    Article  CAS  Google Scholar 

  46. Donega V, et al. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One. 2013;8(1):e51253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yu D, et al. Intranasal delivery of therapeutic stem cells to glioblastoma in a mouse model. J Vis Exp. 2017;(124):e55845.

  48. Zhang Y-T, et al. Advances in intranasal application of stem cells in the treatment of central nervous system diseases. Stem Cell Res Ther. 2021;12(1):1–10.

    Google Scholar 

  49. Liu X, Jia X. Stem cell therapy for ischemic brain injury: early intranasal delivery after cardiac arrest. Transl Stroke Res. 2023:1–3.

  50. Donega V, et al. Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse. Pediatr Res. 2015;78(5):520–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Donega V, et al. Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions. PLoS One. 2014;9(11):e112339.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.

    Article  CAS  PubMed  Google Scholar 

  53. Bremnes RM, et al. High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non–small-cell lung cancer. J Clin Oncol. 2002;20(10):2417–28.

    Article  CAS  PubMed  Google Scholar 

  54. Wichterle H, et al. Directed differentiation of embryonic stem cells into motor neurons. Cell. 2002;110(3):385–97.

    Article  CAS  PubMed  Google Scholar 

  55. Nagai N, et al. Systemic transplantation of embryonic stem cells accelerates brain lesion decrease and angiogenesis. Neuroreport. 2010;21(8):575–9.

    Article  PubMed  Google Scholar 

  56. Tae-Hoon L, Yoon-Seok L. Transplantation of mouse embryonic stem cell after middle cerebral artery occlusion. Acta Cir Bras. 2012;27(4):333–9.

    Article  PubMed  Google Scholar 

  57. Wei L, et al. Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. Neurobiol Dis. 2005;19(1-2):183–93.

    Article  CAS  PubMed  Google Scholar 

  58. Yanagisawa D, et al. Improvement of focal ischemia-induced rat dopaminergic dysfunction by striatal transplantation of mouse embryonic stem cells. Neurosci Lett. 2006;407(1):74–9.

    Article  CAS  PubMed  Google Scholar 

  59. Daadi MM, Maag AL, Steinberg GK. Adherent self-renewable human embryonic stem cell-derived neural stem cell line: functional engraftment in experimental stroke model. PLoS One. 2008;3(2):e1644.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kim DY, et al. Effect of human embryonic stem cell-derived neuronal precursor cell transplantation into the cerebral infarct model of rat with exercise. Neurosci Res. 2007;58(2):164–75.

    Article  CAS  PubMed  Google Scholar 

  61. Bühnemann C, et al. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain. 2006;129(Pt 12):3238–48.

    Article  PubMed  Google Scholar 

  62. Hayashi J, et al. Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. J Cereb Blood Flow Metab. 2006;26(7):906–14.

    Article  PubMed  Google Scholar 

  63. Hicks AU, et al. Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery. Eur J Neurosci. 2009;29(3):562–74.

    Article  PubMed  Google Scholar 

  64. Erdö F, et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab. 2003;23(7):780–5.

    Article  PubMed  Google Scholar 

  65. Seminatore C, et al. The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke. 2010;41(1):153–9.

    Article  PubMed  Google Scholar 

  66. Li F, et al. Combined transplantation of neural stem cells and bone marrow mesenchymal stem cells promotes neuronal cell survival to alleviate brain damage after cardiac arrest via microRNA-133b incorporated in extracellular vesicles. Aging. 2021;13(1):262.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Dulak J, et al. Adult stem cells: hopes and hypes of regenerative medicine. Acta Biochim Pol. 2015;62(3)

  68. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  69. Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. 2007;131(5):861–72.

  70. Nakagawa M, et al. A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. Sci Rep. 2014;4(1):1–7.

    Article  Google Scholar 

  71. Kooreman NG, Wu JC. Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging. J R Soc Interface. 2010;7(suppl_6):S753–63.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Cefalo MG, et al. Human iPSC for therapeutic approaches to the nervous system: present and future applications. Stem Cells Int. 2016;2016:4869071.

    Article  PubMed  Google Scholar 

  73. Ambasudhan R, et al. Potential for cell therapy in Parkinson's disease using genetically programmed human embryonic stem cell–derived neural progenitor cells. J Comp Neurol. 2014;522(12):2845–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yu Y, et al. IPSC-MSC inhibition assessment in Raw 264.7 cells following oxygen and glucose deprivation reveals a distinct function for cardiopulmonary resuscitation. Mol Med Rep. 2018;17(6):8212–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Yu Y, et al. Mesenchymal stem cells derived from induced pluripotent stem cells play a key role in immunomodulation during cardiopulmonary resuscitation. Brain Res. 2019;1720:146293.

    Article  CAS  PubMed  Google Scholar 

  76. Tornero D, et al. Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli. Brain. 2017;140(3):692–706.

    PubMed  Google Scholar 

  77. Jiang M, et al. Induction of pluripotent stem cells transplantation therapy for ischemic stroke. Mol Cell Biochem. 2011;354(1):67–75.

    Article  CAS  PubMed  Google Scholar 

  78. Eckert A, et al. Bystander effect fuels human induced pluripotent stem cell-derived neural stem cells to quickly attenuate early stage neurological deficits after stroke. Stem Cells Transl Med. 2015;4(7):841–51.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Lau VW, et al. Human iNPC therapy leads to improvement in functional neurologic outcomes in a pig ischemic stroke model. Brain Behav. 2018;8(5):e00972.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Baker EW, et al. Induced pluripotent stem cell-derived neural stem cell therapy enhances recovery in an ischemic stroke pig model. Sci Rep. 2017;7(1):1–15.

    Article  Google Scholar 

  81. Okita K, et al. An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells. 2013;31(3):458–66.

    Article  CAS  PubMed  Google Scholar 

  82. Yu J, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324(5928):797–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Oh S-H, et al. Multimodal therapeutic effects of neural precursor cells derived from human-induced pluripotent stem cells through episomal plasmid-based reprogramming in a rodent model of ischemic stroke. Stem Cells Int. 2020;2020:4061516.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Oki K, et al. Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells. 2012;30(6):1120–33.

    Article  CAS  PubMed  Google Scholar 

  85. Chen S-J, et al. Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev. 2010;19(11):1757–67.

    Article  CAS  PubMed  Google Scholar 

  86. Jensen MB, et al. Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J Stroke Cerebrovasc Dis. 2013;22(4):304–8.

    Article  PubMed  Google Scholar 

  87. Kawai H, et al. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab. 2010;30(8):1487–93.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Boldrini M, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22(4):589–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bernstock JD, et al. Neural stem cell transplantation in ischemic stroke: a role for preconditioning and cellular engineering. J Cereb Blood Flow Metab. 2017;37(7):2314–9.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Tang Y, et al. Current progress in the derivation and therapeutic application of neural stem cells. Cell Death Dis. 2017;8(10):e3108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oh JH, et al. Comparative analysis of human embryonic stem cell-derived neural stem cells as an in vitro human model. Int J Mol Med. 2018;41(2):783–90.

    CAS  PubMed  Google Scholar 

  92. Gage FH, Temple SJN. Neural stem cells: generating and regenerating the brain. Neuron. 2013;80(3):588–601.

    Article  CAS  PubMed  Google Scholar 

  93. Meyer P, et al. Grafted Neural progenitor cells persist in the injured site and differentiate neuronally in a rodent model of cardiac arrest-induced global brain ischemia. Stem Cells Dev. 2020;29(9):574–85.

    Article  CAS  PubMed  Google Scholar 

  94. Jin K, et al. Effect of human neural precursor cell transplantation on endogenous neurogenesis after focal cerebral ischemia in the rat. Brain Res. 2011;1374:56–62.

    Article  CAS  PubMed  Google Scholar 

  95. Hassani Z, et al. Human neural progenitor cell engraftment increases neurogenesis and microglial recruitment in the brain of rats with stroke. PLoS One. 2012;7(11):e50444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ryu S, et al. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain. Neural Regen Res. 2016;11(2):298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Stroemer P, et al. The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dose-dependent fashion. Neurorehabil Neural Repair. 2009;23(9):895–909.

    Article  PubMed  Google Scholar 

  98. Mine Y, et al. Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats. Neurobiol Dis. 2013;52:191–203.

    Article  CAS  PubMed  Google Scholar 

  99. Andres RH, et al. Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain. 2011;134(6):1777–89.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Patkar S, et al. Conditionally immortalised neural stem cells promote functional recovery and brain plasticity after transient focal cerebral ischaemia in mice. Stem Cell Res. 2012;8(1):14–25.

    Article  CAS  PubMed  Google Scholar 

  101. Horie N, et al. Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells. 2011;29(2):274–85.

    Article  CAS  PubMed  Google Scholar 

  102. Hicks C, et al. In vivo and in vitro characterization of the angiogenic effect of CTX0E03 human neural stem cells. Cell Transplant. 2013;22(9):1541–52.

    Article  PubMed  Google Scholar 

  103. Darsalia V, Kallur T, Kokaia Z. Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. Eur J Neurosci. 2007;26(3):605–14.

    Article  PubMed  Google Scholar 

  104. Tornero D, et al. Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. Brain. 2013;136(12):3561–77.

    Article  PubMed  Google Scholar 

  105. Kelly S, et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci. 2004;101(32):11839–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog neurobiol. 2016;142:23–44.

    Article  CAS  PubMed  Google Scholar 

  107. Jiang Y, et al. Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat. Mediat Inflamm. 2010;2010:372423.

    Article  Google Scholar 

  108. Lladó J, et al. Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Mol Cell Neurosci. 2004;27(3):322–31.

    Article  PubMed  Google Scholar 

  109. Ourednik J, et al. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol. 2002;20(11):1103–10.

    Article  CAS  PubMed  Google Scholar 

  110. Bacigaluppi M, et al. Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain. 2009;132(8):2239–51.

    Article  PubMed  Google Scholar 

  111. Song M, et al. Long-term effects of magnetically targeted ferumoxide-labeled human neural stem cells in focal cerebral ischemia. Cell Transplant. 2015;24(2):183–90.

    Article  PubMed  Google Scholar 

  112. Watanabe T, et al. A human neural stem cell line provides neuroprotection and improves neurological performance by early intervention of neuroinflammatory system. Brain Res. 2016;1631:194–203.

    Article  CAS  PubMed  Google Scholar 

  113. Li F, et al. miR-26a prevents neural stem cells from apoptosis via β-catenin signaling pathway in cardiac arrest-induced brain damage. Biosci Rep. 2019;39(5)

  114. Kalladka D, et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet. 2016;388(10046):787–96.

    Article  PubMed  Google Scholar 

  115. Qiao LY, Huang FJ, Zhao M, Xie JH, Shi J, Wang J, Lin XZ, Zuo H, Wang YL, Geng TC. A two-year follow-up study of cotransplantation with neural stem/progenitor cells and mesenchymal stromal cells in ischemic stroke patients. Cell Transplant. 2014;23(1_suppl):65–72.

    Article  Google Scholar 

  116. Chen L, et al. Multiple cell transplantation based on an intraparenchymal approach for patients with chronic phase stroke. Cell Transplant. 2013;22(1_suppl):83–91.

    Article  Google Scholar 

  117. Li W, et al. Mesenchymal stem cell-based therapy for stroke: current understanding and challenges. Front Cell Neurosci. 2021;15:628940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Faghih H, Javeri A, Taha MFJC. Impact of early subcultures on stemness, migration and angiogenic potential of adipose tissue-derived stem cells and their resistance to in vitro ischemic condition. Cytotechnology. 2017;69(6):885–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Perteghella S, et al. Fabrication of innovative silk/alginate microcarriers for mesenchymal stem cell delivery and tissue regeneration. Int J Mol Sci. 2017;18(9):1829.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Wang T, et al. Intravenous infusion of bone marrow mesenchymal stem cells improves brain function after resuscitation from cardiac arrest. In: Critical care medicine. LWW; 2008.

    Google Scholar 

  121. Wang T, et al. Improved outcomes of cardiopulmonary resuscitation in rats with myocardial infarction treated with allogenic bone marrow mesenchymal stem cells. Crit Care Med. 2009;37(3):833–9.

    Article  PubMed  Google Scholar 

  122. Wang T, et al. Mesenchymal stem cells improve outcomes of cardiopulmonary resuscitation in myocardial infarcted rats. J Mol Cell Cardiol. 2009;46(3):378–84.

    Article  CAS  PubMed  Google Scholar 

  123. Lin QM, et al. Mesenchymal stem cells transplantation suppresses inflammatory responses in global cerebral ischemia: contribution of TNF-α-induced protein 6. Acta Pharmacol Sin. 2013;34(6):784–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lin Q, et al. Mesenchymal stem cells transplantation improves functional recovery after cardiac arrest: contribution of necroptosis. Chinese J Emerg Med. 2018:39–43.

  125. Harada K, et al. Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model. Brain Res. 2007;1134:206–13.

    Article  CAS  PubMed  Google Scholar 

  126. Zheng W, et al. Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia. Brain Res. 2010;1310:8–16.

    Article  CAS  PubMed  Google Scholar 

  127. Zhou L, et al. Effect and mechanism of different ways of transplanting bone marrow mesenchymal stem cells in cardiopulmonary resuscitation in rats. Genet Mol Res. 2014;13:7937–49.

    Article  CAS  PubMed  Google Scholar 

  128. Leong KH, et al. Therapeutic effects of various methods of MSC transplantation on cerebral resuscitation following cardiac arrest in rats. Mol Med Rep. 2016;13(4):3043–51.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Li G, et al. Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies. Neural Regen Res. 2016;11(6):1015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Moniche F, et al. Increasing dose of autologous bone marrow mononuclear cells transplantation is related to stroke outcome: results from a pooled analysis of two clinical trials. 2016;2016:8657173.

  131. Toyoshima A, et al. Intra-arterial transplantation of allogeneic mesenchymal stem cells mounts neuroprotective effects in a transient ischemic stroke model in rats: analyses of therapeutic time window and its mechanisms. PLoS One. 2015;10(6):e0127302.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Shen LH, 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 

  133. Saraf J, et al. Intra-arterial stem cell therapy modulates neuronal calcineurin and confers neuroprotection after ischemic stroke. Int J Neurosci. 2019;129(10):1039–44.

    Article  CAS  PubMed  Google Scholar 

  134. Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J. 1963;27(3):282–93.

    Article  CAS  PubMed  Google Scholar 

  135. Calió ML, 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  PubMed  Google Scholar 

  136. Kranz A, et al. Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats. Brain Res. 2010;1315:128–36.

    Article  CAS  PubMed  Google Scholar 

  137. Gómez-de Frutos MC, et al. Intravenous delivery of adipose tissue-derived mesenchymal stem cells improves brain repair in hyperglycemic stroke rats. Stem Cell Res Ther. 2019;10(1):1–13.

    Article  Google Scholar 

  138. Cui C, 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  CAS  PubMed  PubMed Central  Google Scholar 

  139. Venkat P, et al. Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats. Exp Neurol. 2020;334:113456.

    Article  CAS  PubMed  Google Scholar 

  140. Wang JW, et al. Transplantation with hypoxia-preconditioned mesenchymal stem cells suppresses brain injury caused by cardiac arrest–induced global cerebral ischemia in rats. J Neurosci Res. 2017;95(10):2059–70.

    Article  CAS  PubMed  Google Scholar 

  141. Zhou L, et al. Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia. Cell Death Dis. 2017;8(5):e2774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Pei Y, et al. Bone marrow mesenchymal stem cells loaded into hydrogel/nanofiber composite scaffolds ameliorate ischemic brain injury. Mater Today Adv. 2023;17:100349.

    Article  CAS  Google Scholar 

  143. Bang OY, et al. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–82.

    Article  PubMed  Google Scholar 

  144. Honmou O, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134(6):1790–807.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Bhasin A, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra. 2011;1(1):93–104.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Jaillard A, et al. Autologous mesenchymal stem cells improve motor recovery in subacute ischemic stroke: a randomized clinical trial. Transl Stroke Res. 2020;11(5):910–23.

    Article  CAS  PubMed  Google Scholar 

  147. Lee JS, et al. 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 

  148. Steinberg GK, 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  PubMed Central  Google Scholar 

  149. Díez-Tejedor E, 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. J Stroke Cerebrovasc Dis. 2014;23(10):2694–700.

    Article  PubMed  Google Scholar 

  150. Laskowitz DT, et al. Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase I safety study. Stem Cells Transl Med. 2018;7(7):521–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Savitz SI, et al. A phase 2 randomized, sham-controlled trial of internal carotid artery infusion of autologous bone marrow–derived ALD-401 cells in patients with recent stable ischemic stroke (RECOVER-Stroke). Circulation. 2019;139(2):192–205.

    Article  PubMed  Google Scholar 

  152. Hess DC, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(5):360–8.

    Article  PubMed  Google Scholar 

  153. Moniche F, et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke. 2012;43(8):2242–4.

    Article  PubMed  Google Scholar 

  154. Prasad K, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45(12):3618–24.

    Article  CAS  PubMed  Google Scholar 

  155. Moniche F, et al. Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial. Lancet Neurol. 2023;22(2):137–46.

    Article  CAS  PubMed  Google Scholar 

  156. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(1):235–42.

    Article  CAS  PubMed  Google Scholar 

  157. Chen N, et al. Human umbilical cord blood cells have trophic effects on young and aging hippocampal neurons in vitro. Aging Dis. 2010;1(3):173.

    PubMed  PubMed Central  Google Scholar 

  158. Roura S, Pujal JM, Bayes-Genis A. Umbilical cord blood for cardiovascular cell therapy: from promise to fact. Ann N Y Acad Sci. 2012;1254(1):66–70.

    Article  CAS  PubMed  Google Scholar 

  159. Rosenkranz K, et al. Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. Cell Tissue Res. 2012;348(3):429–38.

    Article  CAS  PubMed  Google Scholar 

  160. McDonald CA, et al. Effects of umbilical cord blood cells, and subtypes, to reduce neuroinflammation following perinatal hypoxic-ischemic brain injury. J Neuroinflammation. 2018;15(1):1–14.

    Article  Google Scholar 

  161. Leonardo CC, 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. J Neurosci Res. 2010;88(6):1213–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Chen C, Wang Y, Yang G-Y. Stem cell-mediated gene delivering for the treatment of cerebral ischemia: progress and prospectives. Curr Drug Targets. 2013;14(1):81–9.

    Article  CAS  PubMed  Google Scholar 

  163. De Paula S, et al. The dose-response effect of acute intravenous transplantation of human umbilical cord blood cells on brain damage and spatial memory deficits in neonatal hypoxia-ischemia. Neuroscience. 2012;210:431–41.

    Article  PubMed  Google Scholar 

  164. Zhang L, et al. Delayed administration of human umbilical tissue-derived cells improved neurological functional recovery in a rodent model of focal ischemia. Stroke. 2011;42(5):1437–44.

    Article  PubMed  Google Scholar 

  165. Pietras EM, Warr MR, Passegué E. Cell cycle regulation in hematopoietic stem cells. J Cell Biol. 2011;195(5):709–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Schwarting S, et al. Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke. 2008;39(10):2867–75.

    Article  CAS  PubMed  Google Scholar 

  167. Felfly H, et al. Hematopoietic stem cell transplantation protects mice from lethal stroke. Exp Neurol. 2010;225(2):284–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Doycheva D, et al. Granulocyte-colony stimulating factor in combination with stem cell factor confers greater neuroprotection after hypoxic–ischemic brain damage in the neonatal rats than a solitary treatment. Transl Stroke Res. 2013;4(2):171–8.

    Article  CAS  PubMed  Google Scholar 

  169. Hattori T, et al. Administration of umbilical cord blood cells transiently decreased hypoxic-ischemic brain injury in neonatal rats. Dev Neurosci. 2015;37(2):95–104.

    Article  CAS  PubMed  Google Scholar 

  170. de Paula S, et al. Hemispheric brain injury and behavioral deficits induced by severe neonatal hypoxia-ischemia in rats are not attenuated by intravenous administration of human umbilical cord blood cells. Pediatr Res. 2009;65(6):631–5.

    Article  PubMed  Google Scholar 

  171. Fan Y, et al. Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol. 2010;67(4):488–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Chen C, et al. Effect of HMGB1 on the paracrine action of EPC promotes post-ischemic neovascularization in mice. Stem Cells. 2014;32(10):2679–89.

    Article  CAS  PubMed  Google Scholar 

  173. Ma Y, et al. Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice. J Cereb Blood Flow Metab. 2020;40(12):2374–86.

    Article  CAS  PubMed  Google Scholar 

  174. Li Y, et al. cxcl12-engineered endothelial progenitor cells enhance neurogenesis and angiogenesis after ischemic brain injury in mice. Stem Cell Res Ther. 2018;9(1):1–15.

    Article  Google Scholar 

  175. Ichimura H, Chino S, Shiba Y. Cardiac regeneration using pluripotent stem cells and controlling immune responses. Heart Lung Circ. 2023;

  176. Kitano Y, et al. Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR-Cas9 system and detailed evaluation for clinical application. Mol Ther Methods Clin Dev. 2022;26:15–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Hosseini SR, Hashemi-Najafabadi S, Bagheri F. Differentiation of the mesenchymal stem cells to pancreatic β-like cells in alginate/trimethyl chitosan/alginate microcapsules. Prog Biomat. 2022;11(3):273–80.

    Article  CAS  Google Scholar 

  178. Lin Q, et al. Expression of tumor necrosis factor-α-induced protein 6 after transplantation of mesenchymal stem cells in a rat model of cardiopulmonary resuscitation. Chinese J Emerg Med. 2014:1098–104.

  179. Lu S, et al. Optimization of an intranasal route for the delivery of human neural stem cells to treat a neonatal hypoxic-ischemic brain injury rat model. Neuropsychiatr Dis Treat. 2022;18:413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hu Y, et al. Hypoxic preconditioning improves the survival and neural effects of transplanted mesenchymal stem cells via CXCL12/CXCR4 signalling in a rat model of cerebral infarction. Cell Biochem Funct. 2019;37(7):504–15.

    Article  CAS  PubMed  Google Scholar 

  181. McDonald CA, et al. Intranasal delivery of mesenchymal stromal cells protects against neonatal hypoxic–ischemic brain injury. Int J Mol Sci. 2019;20(10):2449.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was partially supported by R01NS125232 and R01NS110387 from the United States National Institute of Health (both to Xiaofeng Jia).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Xiao Liu & Xiaofeng Jia

  2. Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Xiaofeng Jia

  3. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Xiaofeng Jia

  4. Department of Biomedical Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Xiaofeng Jia

Authors
  1. Xiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaofeng Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xiao Liu searched and reviewed the literature, drafted the manuscript, and worked on the revision; Xiaofeng Jia designed and formulated the review theme, viewed the literature, and revised and finalized the manuscript.

Corresponding author

Correspondence to Xiaofeng Jia.

Ethics declarations

Ethics Approval

N/A.

Human and Animal Ethics

N/A.

Consent for Publication

All authors have approved and given the content for the publication.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Jia, X. Neuroprotection of Stem Cells Against Ischemic Brain Injury: From Bench to Clinic. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01163-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12975-023-01163-3

Keywords

Search

Navigation