Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

  • Elena Abati
  • Nereo Bresolin
  • Giacomo Pietro Comi
  • Stefania CortiEmail author


Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders.


Stem cell transplantation Stem cells Neural stem cells Cellular engineering Preconditioning Motor neuron diseases Amyotrophic lateral sclerosis Spinal muscular atrophy 



amyotrophic lateral sclerosis


brain-derived neurotrophic factor


central nervous system


glial-derived neurotrophic factor


high-mobility group box 1


induced pluripotent stem cell


major histocompatibility complex


motor neuron disorder


nerve growth factor


neural progenitor cell


neural stem cell


spinal muscular atrophy


spinal muscular atrophy with respiratory distress type 1


vascular endothelial growth facto



The following grant support is gratefully acknowledged: Italian Ministry of Health–RF-2016-02362317 and AFM-Telethon-2015, “Optimized Transplantation of hiPSC-derived LeX+CXCR4+VLA4 neural stem cells as a therapy for SMARD1” to GPC, and FP7-PEOPLE-2013-IRSES no. 612578 to SC. We thank the Associazione Amici del Centro Dino Ferrari for its support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hardiman O, Al-Chalabi A, Chio A et al (2017) Amyotrophic lateral sclerosis. Nat Publ Gr 3:17085. CrossRefGoogle Scholar
  2. 2.
    Lacomblez L, Bensimon G, Leigh PN, et al (1996) Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet (London, England) 347:1425–31Google Scholar
  3. 3.
    Abe K, Aoki M, Tsuji S, Itoyama Y, Sobue G, Togo M, Hamada C, Tanaka M et al (2017) Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 16:505–512. CrossRefGoogle Scholar
  4. 4.
    Parente V, Corti S (2018) Advances in spinal muscular atrophy therapeutics. Ther Adv Neurol Disord 11:175628561875450. CrossRefGoogle Scholar
  5. 5.
    Chen KS, Sakowski SA, Feldman EL (2016) Intraspinal stem cell transplantation for amyotrophic lateral sclerosis. Ann Neurol 79:342–353. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gilbert SF (2000) Developmental biology. Sinauer AssociatesGoogle Scholar
  7. 7.
    Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335CrossRefPubMedGoogle Scholar
  8. 8.
    Kornack DR, Rakic P (1999) Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci U S A 96:5768–5773CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153–7160CrossRefPubMedGoogle Scholar
  10. 10.
    Patzke N, Spocter MA, Karlsson KÆ, Bertelsen MF, Haagensen M, Chawana R, Streicher S, Kaswera C et al (2015) In contrast to many other mammals, cetaceans have relatively small hippocampi that appear to lack adult neurogenesis. Brain Struct Funct 220:361–383. CrossRefPubMedGoogle Scholar
  11. 11.
    Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386:493–495. CrossRefPubMedGoogle Scholar
  12. 12.
    Hill AS, Sahay A, Hen R (2015) Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology 40:2368–2378. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317. CrossRefPubMedGoogle Scholar
  14. 14.
    Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S et al (2018) Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555:377–381. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Boldrini M, Fulmore CA, Tartt AN, et al (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22:589–599.e5. doi:
  16. 16.
    Sabelström H, Stenudd M, Frisén J (2014) Neural stem cells in the adult spinal cord. Exp Neurol 260:44–49. CrossRefPubMedGoogle Scholar
  17. 17.
    Liu Z, Martin LJ (2006) The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain. J Comp Neurol 497:468–488. CrossRefPubMedGoogle Scholar
  18. 18.
    Chi L, Gan L, Luo C, Lien L, Liu R (2007) Temporal response of neural progenitor cells to disease onset and progression in amyotrophic lateral sclerosis-like transgenic mice. Stem Cells Dev 16:579–588. CrossRefPubMedGoogle Scholar
  19. 19.
    Kojima T, Hirota Y, Ema M, Takahashi S, Miyoshi I, Okano H, Sawamoto K (2010) Subventricular zone-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells 28:545–554. PubMedCrossRefGoogle Scholar
  20. 20.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970. CrossRefPubMedGoogle Scholar
  21. 21.
    Khodanovich M, Kisel A, Kudabaeva M, Chernysheva G, Smolyakova V, Krutenkova E, Wasserlauf I, Plotnikov M et al (2018) Effects of fluoxetine on hippocampal neurogenesis and neuroprotection in the model of global cerebral ischemia in rats. Int J Mol Sci 19:162. CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M et al (2003) Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53:743–751. CrossRefPubMedGoogle Scholar
  23. 23.
    Corbett AM, Sieber S, Wyatt N, Lizzi J, Flannery T, Sibbit B, Sanghvi S (2015) Increasing neurogenesis with fluoxetine, simvastatin and ascorbic acid leads to functional recovery in ischemic stroke. Recent Pat Drug Deliv Formul 9:158–166CrossRefPubMedGoogle Scholar
  24. 24.
    Dametti S, Faravelli I, Ruggieri M, Ramirez A, Nizzardo M, Corti S (2016) Experimental advances towards neural regeneration from induced stem cells to direct in vivo reprogramming. Mol Neurobiol 53:2124–2131. CrossRefPubMedGoogle Scholar
  25. 25.
    Faravelli I, Riboldi G, Nizzardo M, Simone C, Zanetta C, Bresolin N, Comi GP, Corti S (2014) Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation. Cell Mol Life Sci 71:3257–3268. CrossRefPubMedGoogle Scholar
  26. 26.
    Nizzardo M, Simone C, Rizzo F, Ruggieri M, Salani S, Riboldi G, Faravelli I, Zanetta C et al (2014) Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA4+ neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model. Hum Mol Genet 23:342–354. CrossRefPubMedGoogle Scholar
  27. 27.
    Nizzardo M, Bucchia M, Ramirez A, Trombetta E, Bresolin N, Comi GP, Corti S (2016) iPSC-derived LewisX+CXCR4+β1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models. Hum Mol Genet 25:3152–3163. CrossRefPubMedGoogle Scholar
  28. 28.
    Corti S, Locatelli F, Papadimitriou D, Donadoni C, del Bo R, Crimi M, Bordoni A, Fortunato F et al (2006) Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. Hum Mol Genet 15:167–187. CrossRefPubMedGoogle Scholar
  29. 29.
    Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, Ronchi D, Simone C, Falcone M et al (2010) Embryonic stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice. Brain 133:465–481. CrossRefPubMedGoogle Scholar
  30. 30.
    Simone C, Nizzardo M, Rizzo F, Ruggieri M, Riboldi G, Salani S, Bucchia M, Bresolin N et al (2014) iPSC-derived neural stem cells act via kinase inhibition to exert neuroprotective effects in spinal muscular atrophy with respiratory distress type 1. Stem Cell Reports 3:297–311. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Teng YD, Benn SC, Kalkanis SN et al (2012) Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Sci Transl Med 4:165ra164. CrossRefPubMedGoogle Scholar
  32. 32.
    Bliss T, Guzman R, Daadi M, Steinberg GK (2007) Cell transplantation therapy for stroke. Stroke 38:817–826. CrossRefPubMedGoogle Scholar
  33. 33.
    Wakai T, Narasimhan P, Sakata H, Wang E, Yoshioka H, Kinouchi H, Chan PH (2016) Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab 36:2134–2145. CrossRefPubMedGoogle Scholar
  34. 34.
    Xu L, Shen P, Hazel T, Johe K, Koliatsos VE (2011) Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci Lett 494:222–226. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kim KS, Lee HJ, An J, Kim YB, Ra JC, Lim I, Kim SU (2014) Transplantation of human adipose tissue-derived stem cells delays clinical onset and prolongs life span in ALS mouse model. Cell Transplant 23:1585–1597. CrossRefPubMedGoogle Scholar
  36. 36.
    Eve DJ, Steiner G, Mahendrasah A, et al (2018) Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier. Oncotarget 9:10621–10634. doi:
  37. 37.
    Sironi F, Vallarola A, Violatto MB, Talamini L, Freschi M, de Gioia R, Capelli C, Agostini A et al (2017) Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice. Stem Cell Res 25:166–178. CrossRefPubMedGoogle Scholar
  38. 38.
    Riley J, Federici T, Polak M, Kelly C, Glass J, Raore B, Taub J, Kesner V et al (2012) Intraspinal stem cell transplantation in amyotrophic lateral sclerosis. Neurosurgery 71:405–416. CrossRefPubMedGoogle Scholar
  39. 39.
    Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T, Polak M, Kelly C, Feldman EL (2012) Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 30:1144–1151. CrossRefPubMedGoogle Scholar
  40. 40.
    Feldman EL, Boulis NM, Hur J, Johe K, Rutkove SB, Federici T, Polak M, Bordeau J et al (2014) Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol 75:363–373. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Glass JD, Hertzberg VS, Boulis NM, Riley J, Federici T, Polak M, Bordeau J, Fournier C et al (2016) Transplantation of spinal cord–derived neural stem cells for ALS. Neurology 87:392–400. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Goutman SA, Brown MB, Glass JD, Boulis NM, Johe K, Hazel T, Cudkowicz M, Atassi N et al (2018) Long-term phase 1/2 intraspinal stem cell transplantation outcomes in ALS. Ann Clin Transl Neurol 5:730–740. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Barker RA, Widner H (2004) Immune problems in central nervous system cell therapy. NeuroRX 1:472–481. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Tadesse T, Gearing M, Senitzer D, Saxe D, Brat DJ, Bray R, Gebel H, Hill C et al (2014) Analysis of graft survival in a trial of stem cell transplant in ALS. Ann Clin Transl Neurol 1:900–908. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H et al (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 71:999–1015. CrossRefPubMedGoogle Scholar
  47. 47.
    Srivastava AK, Gross SK, Almad AA, Bulte CA, Maragakis NJ, Bulte JWM (2017) Serial in vivo imaging of transplanted allogeneic neural stem cell survival in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 289:96–102. CrossRefPubMedGoogle Scholar
  48. 48.
    Hori J, Ng TF, Shatos M, Klassen H, Streilein JW, Young MJ (2003) Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 21:405–416. CrossRefPubMedGoogle Scholar
  49. 49.
    Bakshi A, Keck CA, Koshkin VS, LeBold DG, Siman R, Snyder EY, McIntosh TK (2005) Caspase-mediated cell death predominates following engraftment of neural progenitor cells into traumatically injured rat brain. Brain Res 1065:8–19. CrossRefPubMedGoogle Scholar
  50. 50.
    Yu SP, Wei Z, Wei L (2013) Preconditioning strategy in stem cell transplantation therapy. Transl Stroke Res 4:76–88. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bernstock JD, Peruzzotti-Jametti L, Ye D, Gessler FA, Maric D, Vicario N, Lee YJ, Pluchino S et al (2017) Neural stem cell transplantation in ischemic stroke: a role for preconditioning and cellular engineering. J Cereb Blood Flow Metab 37:2314–2319. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Sandvig I, Gadjanski I, Vlaski-Lafarge M, Buzanska L, Loncaric D, Sarnowska A, Rodriguez L, Sandvig A et al (2017) Strategies to enhance implantation and survival of stem cells after their injection in ischemic neural tissue. Stem Cells Dev 26:554–565. CrossRefPubMedGoogle Scholar
  53. 53.
    Fan W-L, Liu P, Wang G, Pu JG, Xue X, Zhao JH (2017) Transplantation of hypoxic preconditioned neural stem cells benefits functional recovery via enhancing neurotrophic secretion after spinal cord injury in rats. J Cell Biochem 119:4339–4351. CrossRefGoogle Scholar
  54. 54.
    Zhang G, Chen L, Guo X, Wang H, Chen W, Wu G, Gu B, Miao W et al (2018) Comparative analysis of microRNA expression profiles of exosomes derived from normal and hypoxic preconditioning human neural stem cells by next generation sequencing. J Biomed Nanotechnol 14:1075–1089. CrossRefPubMedGoogle Scholar
  55. 55.
    Sakata H, Niizuma K, Yoshioka H, Kim GS, Jung JE, Katsu M, Narasimhan P, Maier CM et al (2012) Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 32:3462–3473. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sakata H, Narasimhan P, Niizuma K, Maier CM, Wakai T, Chan PH (2012) Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice. Brain 135:3298–3310. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Rosenblum S, Smith TN, Wang N, Chua JY, Westbroek E, Wang K, Guzman R (2015) BDNF pretreatment of human embryonic-derived neural stem cells improves cell survival and functional recovery after transplantation in hypoxic-ischemic stroke. Cell Transplant 24:2449–2461. CrossRefPubMedGoogle Scholar
  58. 58.
    Cheng Y-H, Xia W, Wong EWP, Xie Q, Shao J, Liu T, Quan Y, Zhang T et al (2015) Adjudin--a male contraceptive with other biological activities. Recent Pat Endocr Metab Immune Drug Discov 9:63–73CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Shao J, Liu T, Xie QR, Zhang T, Yu H, Wang B, Ying W, Mruk DD et al (2013) Adjudin attenuates lipopolysaccharide (LPS)- and ischemia-induced microglial activation. J Neuroimmunol 254:83–90. CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang T, Yang X, Liu T, Shao J, Fu N, Yan A, Geng K, Xia W (2017) Adjudin-preconditioned neural stem cells enhance neuroprotection after ischemia reperfusion in mice. Stem Cell Res Ther 8:248. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Xue X, Chen X, Fan W, Wang G, Zhang L, Chen Z, Liu P, Liu M et al (2018) High-mobility group box 1 facilitates migration of neural stem cells via receptor for advanced glycation end products signaling pathway. Sci Rep 8:4513. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Ould-Brahim F, Sarma SN, Syal C, et al (2018) Metformin preconditioning of human induced pluripotent stem cell-derived neural stem cells promotes their engraftment and improves post-stroke regeneration and recovery. Stem Cells Dev scd.2018.0055. doi:
  63. 63.
    Degterev A, Linkermann A (2016) Generation of small molecules to interfere with regulated necrosis. Cell Mol Life Sci 73:2251–2267. CrossRefPubMedGoogle Scholar
  64. 64.
    Zhong J, Chan A, Morad L, Kornblum HI, Guoping Fan, Carmichael ST (2010) Hydrogel matrix to support stem cell survival after brain transplantation in stroke. Neurorehabil Neural Repair 24:636–644. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Adil MM, Vazin T, Ananthanarayanan B, Rodrigues GMC, Rao AT, Kulkarni RU, Miller EW, Kumar S et al (2017) Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons. Biomaterials 136:1–11. CrossRefPubMedGoogle Scholar
  66. 66.
    Moshayedi P, Nih LR, Llorente IL, Berg AR, Cinkornpumin J, Lowry WE, Segura T, Carmichael ST (2016) Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain. Biomaterials 105:145–155. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Somaa FA, Wang T-Y, Niclis JC, Bruggeman KF, Kauhausen JA, Guo H, McDougall S, Williams RJ et al (2017) Peptide-based scaffolds support human cortical progenitor graft integration to reduce atrophy and promote functional repair in a model of stroke. Cell Rep 20:1964–1977. CrossRefPubMedGoogle Scholar
  68. 68.
    George PM, Bliss TM, Hua T, Lee A, Oh B, Levinson A, Mehta S, Sun G et al (2017) Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery. Biomaterials 142:31–40. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Gowing G, Svendsen S, Svendsen CN (2017) Ex vivo gene therapy for the treatment of neurological disorders. In: Progress in brain research. pp 99–132Google Scholar
  70. 70.
    Andsberg G, Kokaia Z, Björklund A, Lindvall O, Martínez-Serrano A (1998) Amelioration of ischaemia-induced neuronal death in the rat striatum by NGF-secreting neural stem cells. Eur J Neurosci 10:2026–2036CrossRefPubMedGoogle Scholar
  71. 71.
    Chang D-J, Lee N, Choi C, Jeon I, Oh SH, Shin DA, Hwang TS, Lee HJ et al (2013) Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) in a rodent model of middle cerebral artery occlusion. Cell Transplant 22:1441–1452. CrossRefPubMedGoogle Scholar
  72. 72.
    Zhang Z-H, Wang R-Z, Wang R-Z, Li GL, Wei JJ, Li ZJ, Feng M, Kang J et al (2008) Transplantation of neural stem cells modified by human neurotrophin-3 promotes functional recovery after transient focal cerebral ischemia in rats. Neurosci Lett 444:227–230. CrossRefPubMedGoogle Scholar
  73. 73.
    Chen B, Gao X-Q, Yang C-X, Tan SK, Sun ZL, Yan NH, Pang YG, Yuan M et al (2009) Neuroprotective effect of grafting GDNF gene-modified neural stem cells on cerebral ischemia in rats. Brain Res 1284:1–11. CrossRefPubMedGoogle Scholar
  74. 74.
    Zhu W, Mao Y, Zhao Y, Zhou LF, Wang Y, Zhu JH, Zhu Y, Yang GY (2005) Transplantation of vascular endothelial growth factor-transfected neural stem cells into the rat brain provides neuroprotection after transient focal cerebral ischemia. Neurosurgery 57:325–333 discussion 325-33CrossRefPubMedGoogle Scholar
  75. 75.
    Zhu J, Zhao Y, Chen S, Zhang WH, Lou L, Jin X (2011) Functional recovery after transplantation of neural stem cells modified by brain-derived neurotrophic factor in rats with cerebral ischaemia. J Int Med Res 39:488–498. CrossRefPubMedGoogle Scholar
  76. 76.
    Thomsen GM, Avalos P, Ma AA, Alkaslasi M, Cho N, Wyss L, Vit JP, Godoy M et al (2018) Transplantation of neural progenitor cells expressing glial cell line-derived neurotrophic factor into the motor cortex as a strategy to treat amyotrophic lateral sclerosis. Stem Cells 36:1122–1131. CrossRefGoogle Scholar
  77. 77.
    Sakata H, Niizuma K, Wakai T, Narasimhan P, Maier CM, Chan PH (2012) Neural stem cells genetically modified to overexpress cu/Zn-superoxide dismutase enhance amelioration of ischemic stroke in mice. Stroke 43:2423–2429. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Yang W, Sheng H, Wang H (2016) Targeting the SUMO pathway for neuroprotection in brain ischaemia. BMJ 1:101–107. CrossRefGoogle Scholar
  79. 79.
    Theus MH, Wei L, Cui L, Francis K, Hu X, Keogh C, Yu SP (2008) In vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain. Exp Neurol 210:656–670. CrossRefPubMedGoogle Scholar
  80. 80.
    Wei L, Fraser JL, Lu Z-Y, Hu X, Yu SP (2012) Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 46:635–645. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Sun J, Wei ZZ, Gu X, Zhang JY, Zhang Y, Li J, Wei L (2015) Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice. Exp Neurol 272:78–87. CrossRefPubMedGoogle Scholar
  82. 82.
    Wei ZZ, Lee JH, Zhang Y, Zhu YB, Deveau TC, Gu X, Winter MM, Li J et al (2016) Intracranial transplantation of hypoxia-preconditioned iPSC-derived neural progenitor cells alleviates neuropsychiatric defects after traumatic brain injury in juvenile rats. Cell Transplant 25:797–809. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience SectionUniversity of MilanMilanItaly
  2. 2.Neurology UnitFoundation IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly

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