Molecular Neurobiology

, Volume 56, Issue 10, pp 6703–6715 | Cite as

Advances, Challenges, and Perspectives in Translational Stem Cell Therapy for Amyotrophic Lateral Sclerosis

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


Finding an effective therapeutic approach is a primary goal for current and future research for amyotrophic lateral sclerosis (ALS), a fatal neurological disease characterized by degeneration and loss of upper and lower motor neurons. Transplantation approaches based on stem cells have been attempted in virtue of their potential to contrast simultaneously different ALS pathogenic aspects including either the replacement of lost cells or the protection of motor neurons from degeneration and toxic microenvironment. Here, we critically review the recent translational research aimed at the assessment of stem cell transplantation safety and feasibility in the treatment of ALS. Most of these efforts aim to exert a neuroprotective action rather than cell replacement. Critical aspects that emerge in these studies are the need for the identification of the most effective therapeutic cell source (mesenchymal stem cells, immune, or neural stem cells), the definition of the optimal injection site (cortical area, spinal cord, or muscles) with a suitable administration protocol (local or systemic injection), and the analysis of therapeutic mechanisms, which are necessary steps in order to overcome the hurdles posed by previous in vivo human studies. New perspectives will also be offered by the increasing number of induced pluripotent stem cell-based therapies that are now being tested in clinical trials. A thorough analysis of recently completed trials is the foundation for continued progress in cellular therapy for ALS and other neurodegenerative disorders.


Amyotrophic lateral sclerosis Motor neuron Mesenchymal stem cells Regulatory T cells Neural stem cells Induced pluripotent stem cells Stem cell transplantation 



We thank the Associazione Amici del Centro Dino Ferrari for its support. The figure was modified from images from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License.

Funding information

The following grant supports are 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 CROSS-NEUROD Grant ID: 778003 to SC.

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 Rev Dis Primers 3:17071. CrossRefGoogle Scholar
  2. 2.
    Brown RH, Al-Chalabi A (2017) Amyotrophic lateral sclerosis. N Engl J Med 377:162–172. CrossRefGoogle Scholar
  3. 3.
    Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev:CD001447.
  4. 4.
    Bucchia M, Ramirez A, Parente V, Simone C, Nizzardo M, Magri F, Dametti S, Corti S (2015) Therapeutic development in amyotrophic lateral sclerosis. Clin Ther 37:668–680. CrossRefGoogle Scholar
  5. 5.
    Al-Chalabi A, Andersen PM, Chandran S et al (2017) July 2017 ENCALS statement on edaravone. Amyotroph Lateral Scler Frontotemporal Degener 18:471–474. CrossRefGoogle Scholar
  6. 6.
    Crisafulli SG, Brajkovic S, Cipolat Mis MS, Parente V, Corti S (2018) Therapeutic strategies under development targeting inflammatory mechanisms in amyotrophic lateral sclerosis. Mol Neurobiol 55:2789–2813. CrossRefGoogle Scholar
  7. 7.
    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. CrossRefGoogle Scholar
  8. 8.
    Abati E, Bresolin N, Pietro CG, Corti S (2018) Preconditioning and cellular engineering to increase the survival of transplanted neural stem cells for motor neuron disease therapy. Mol Neurobiol.
  9. 9.
    Sakowski SA, Schuyler AD, Feldman EL (2009) Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10:63–73. CrossRefGoogle Scholar
  10. 10.
    Javorkova E, Matejckova N, Zajicova A, Hermankova B, Hajkova M, Bohacova P, Kossl J, Krulova M et al (2018) Immunomodulatory properties of bone marrow mesenchymal stem cells from patients with amyotrophic lateral sclerosis and healthy donors. J NeuroImmune Pharmacol.
  11. 11.
    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. CrossRefGoogle Scholar
  12. 12.
    Mazzini L, Ferrari D, Andjus PR, Buzanska L, Cantello R, de Marchi F, Gelati M, Giniatullin R et al (2018) Advances in stem cell therapy for amyotrophic lateral sclerosis. Expert Opin Biol Ther 18:865–881. CrossRefGoogle Scholar
  13. 13.
    Baloh RH, Glass JD, Svendsen CN (2018) Stem cell transplantation for amyotrophic lateral sclerosis. Curr Opin Neurol 31:655–661. CrossRefGoogle Scholar
  14. 14.
    Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, Johe K, Koliatsos VE (2007) Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med 4:e39. CrossRefGoogle Scholar
  15. 15.
    Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE (2009) Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J Comp Neurol 514:297–309. CrossRefGoogle Scholar
  16. 16.
    Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, del Bo R, Papadimitriou D, Locatelli F et al (2009) Motoneuron transplantation rescues the phenotype of SMARD1 (spinal muscular atrophy with respiratory distress type 1). J Neurosci 29:11761–11771. CrossRefGoogle Scholar
  17. 17.
    Bonner JF, Blesch A, Neuhuber B, Fischer I (2010) Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J Neurosci Res 88:1182–1192. Google Scholar
  18. 18.
    Silani V, Calzarossa C, Cova L, Ticozzi N (2010) Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement? CNS Neurol Disord Drug Targets 9:314–324CrossRefGoogle Scholar
  19. 19.
    Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song SW, Likhite S et al (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828. CrossRefGoogle Scholar
  20. 20.
    Clement AM, Nguyen MD, Roberts EA et al (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117. CrossRefGoogle Scholar
  21. 21.
    Lepore AC, O’Donnell J, Kim AS et al (2011) Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. PLoS One 6:e25968. CrossRefGoogle Scholar
  22. 22.
    Nicaise C, Mitrecic D, Falnikar A, Lepore AC (2015) Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. World J Stem Cells 7:380–398. CrossRefGoogle Scholar
  23. 23.
    Fischer LR, Glass JD (2007) Axonal degeneration in motor neuron disease. Neurodegener Dis 4:431–442. CrossRefGoogle Scholar
  24. 24.
    Kaspar BK, Lladó J, Sherkat N, Rothstein JD, Gage FH (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839–842. CrossRefGoogle Scholar
  25. 25.
    Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, Cao M, Corti S et al (2016) Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS. Sci Rep 6:25960. CrossRefGoogle Scholar
  26. 26.
    Suzuki M, McHugh J, Tork C, Shelley B, Klein SM, Aebischer P, Svendsen CN (2007) GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS One 2:e689. CrossRefGoogle Scholar
  27. 27.
    Li X, Hacker M (2017) Molecular imaging in stem cell-based therapies of cardiac diseases. Adv Drug Deliv Rev 120:71–88. CrossRefGoogle Scholar
  28. 28.
    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. CrossRefGoogle Scholar
  29. 29.
    Corti S, Faravelli I, Cardano M, Conti L (2015) Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery. Expert Opin Drug Discovery 10:615–629. CrossRefGoogle Scholar
  30. 30.
    Sareen D, Gowing G, Sahabian A, Staggenborg K, Paradis R, Avalos P, Latter J, Ornelas L et al (2014) Human induced pluripotent stem cells are a novel source of neural progenitor cells (iNPCs) that migrate and integrate in the rodent spinal cord. J Comp Neurol 522:2707–2728. CrossRefGoogle Scholar
  31. 31.
    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. CrossRefGoogle Scholar
  32. 32.
    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. CrossRefGoogle Scholar
  33. 33.
    Kavyasudha C, Macrin D, ArulJothi KN et al (2018) Clinical applications of induced pluripotent stem cells - Stato Attuale. Adv Exp Med Biol 1079:127–149. CrossRefGoogle Scholar
  34. 34.
    Mansour AA, Gonçalves JT, Bloyd CW et al (2018) An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol 36:432–441. CrossRefGoogle Scholar
  35. 35.
    Bianco P (2014) “Mesenchymal” stem cells. Annu Rev Cell Dev Biol 30:677–704. CrossRefGoogle Scholar
  36. 36.
    Lindner M, Klotz L, Wiendl H (2018) Mechanisms underlying lesion development and lesion distribution in CNS autoimmunity. J Neurochem 146:122–132. CrossRefGoogle Scholar
  37. 37.
    Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, Simone C, Falcone M, Riboldi G et al (2010) Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis. Hum Mol Genet 19:3782–3796. CrossRefGoogle Scholar
  38. 38.
    Lamanna JJ, Miller JH, Riley JP, Hurtig CV, Boulis NM (2013) Cellular therapeutics delivery to the spinal cord: technical considerations for clinical application. Ther Deliv 4:1397–1410. CrossRefGoogle Scholar
  39. 39.
    Squires A, Oshinski JN, Boulis NM, Tse ZTH (2018) SpinoBot: an MRI-guided needle positioning system for spinal cellular therapeutics. Ann Biomed Eng 46:475–487. CrossRefGoogle Scholar
  40. 40.
    Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H et al (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 344:710–719. CrossRefGoogle Scholar
  41. 41.
    Staff NP, Madigan NN, Morris J et al (2016) Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology 87:2230–2234. CrossRefGoogle Scholar
  42. 42.
    Robey P (2017) “Mesenchymal stem cells”: fact or fiction, and implications in their therapeutic use. F1000Res 6:524. CrossRefGoogle Scholar
  43. 43.
    Sipp D, Robey PG, Turner L (2018) Clear up this stem-cell mess. Nature 561:455–457. CrossRefGoogle Scholar
  44. 44.
    Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, Pastore I, Marasso R et al (2003) Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotroph Lateral Scler Other Motor Neuron Disord 4:158–161CrossRefGoogle Scholar
  45. 45.
    Ciervo Y, Ning K, Jun X, Shaw PJ, Mead RJ (2017) Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis. Mol Neurodegener 12:85. CrossRefGoogle Scholar
  46. 46.
    Ng F, Boucher S, Koh S, Sastry KSR, Chase L, Lakshmipathy U, Choong C, Yang Z et al (2008) PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood 112:295–307. CrossRefGoogle Scholar
  47. 47.
    Syková E, Rychmach P, Drahorádová I, Konrádová ŠI, Růžičková K, Voříšek I, Forostyak S, Homola A et al (2017) Transplantation of mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: results of phase I/IIa clinical trial. Cell Transplant 26:647–658. CrossRefGoogle Scholar
  48. 48.
    Oh K-W, Moon C, Kim HY, Oh SI, Park J, Lee JH, Chang IY, Kim KS et al (2015) Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med 4:590–597. CrossRefGoogle Scholar
  49. 49.
    Gothelf Y, Kaspi H, Abramov N, Aricha R (2017) miRNA profiling of NurOwn®: mesenchymal stem cells secreting neurotrophic factors. Stem Cell Res Ther 8:249. CrossRefGoogle Scholar
  50. 50.
    Petrou P, Gothelf Y, Argov Z, Gotkine M, Levy YS, Kassis I, Vaknin-Dembinsky A, Ben-Hur T et al (2016) Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: results of phase 1/2 and 2a clinical trials. JAMA Neurol 73:337–344. CrossRefGoogle Scholar
  51. 51.
    Daley GQ (2012) The promise and perils of stem cell therapeutics. Cell Stem Cell 10:740–749. CrossRefGoogle Scholar
  52. 52.
    Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I et al (2017) Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 377:2545–2554. CrossRefGoogle Scholar
  53. 53.
    Corti S, Locatelli F, Donadoni C, Guglieri M, Papadimitriou D, Strazzer S, del Bo R, Comi GP (2004) Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain 127:2518–2532. CrossRefGoogle Scholar
  54. 54.
    Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR et al (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:16021–16026. CrossRefGoogle Scholar
  55. 55.
    Thonhoff JR, Simpson EP, Appel SH (2018) Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis. Curr Opin Neurol 31:635–639. CrossRefGoogle Scholar
  56. 56.
    Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A et al (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7:315ra189–315ra189. CrossRefGoogle Scholar
  57. 57.
    Beers DR, Henkel JS, Zhao W, Wang J, Appel SH (2008) CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci 105:15558–15563. CrossRefGoogle Scholar
  58. 58.
    Zhao W, Beers DR, Liao B, Henkel JS, Appel SH (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis 48:418–428. CrossRefGoogle Scholar
  59. 59.
    Thonhoff JR, Beers DR, Zhao W, Pleitez M, Simpson EP, Berry JD, Cudkowicz ME, Appel SH (2018) Expanded autologous regulatory T-lymphocyte infusions in ALS: a phase I, first-in-human study. Neurol Neuroimmunol Neuroinflamm 5:e465. CrossRefGoogle Scholar
  60. 60.
    Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M, Muzi G, Ricciolini C, Rota Nodari L et al (2015) Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med 13:17. CrossRefGoogle Scholar
  61. 61.
    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. CrossRefGoogle Scholar
  62. 62.
    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. CrossRefGoogle Scholar
  63. 63.
    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. CrossRefGoogle Scholar
  64. 64.
    Guo X, Johe K, Molnar P, Davis H, Hickman J (2010) Characterization of a human fetal spinal cord stem cell line, NSI-566RSC, and its induction to functional motoneurons. J Tissue Eng Regen Med 4:181–193. CrossRefGoogle Scholar
  65. 65.
    Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, Hatfield G, Koliatsos VE (2006) Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82:865–875. CrossRefGoogle Scholar
  66. 66.
    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. CrossRefGoogle Scholar
  67. 67.
    Fournier CN, Schoenfeld D, Berry JD, Cudkowicz ME, Chan J, Quinn C, Brown RH, Salameh JS et al (2018) An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 19:242–249. CrossRefGoogle Scholar
  68. 68.
    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
  69. 69.
    Boulis NM, Federici T, Glass JD, Lunn JS, Sakowski SA, Feldman EL (2012) Translational stem cell therapy for amyotrophic lateral sclerosis. Nat Rev Neurol 8:172–176. CrossRefGoogle Scholar
  70. 70.
    (2018) Voices: crossing the valley of death. Cell Stem Cell 23:639–641.
  71. 71.
    King NM, Perrin J (2014) Ethical issues in stem cell research and therapy. Stem Cell Res Ther 5:85. CrossRefGoogle Scholar
  72. 72.
    Henderson GE, Churchill LR, Davis AM, Easter MM, Grady C, Joffe S, Kass N, King NMP et al (2007) Clinical trials and medical care: defining the therapeutic misconception. PLoS Med 4:e324. CrossRefGoogle Scholar
  73. 73.
    Berkowitz AL, Miller MB, Mir SA, Cagney D, Chavakula V, Guleria I, Aizer A, Ligon KL et al (2016) Glioproliferative lesion of the spinal cord as a complication of “stem-cell tourism”. N Engl J Med 375:196–198. CrossRefGoogle Scholar
  74. 74.
    Barker RA, Widner H (2004) Immune problems in central nervous system cell therapy. NeuroRX 1:472–481. CrossRefGoogle Scholar
  75. 75.
    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. CrossRefGoogle Scholar
  76. 76.
    Poesen K, De Schaepdryver M, Stubendorff B et al (2017) Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 88:2302–2309. CrossRefGoogle Scholar
  77. 77.
    McCombe PA, Pfluger C, Singh P et al (2015) Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis. J Neurol Sci 353:122–129. CrossRefGoogle Scholar
  78. 78.
    Escorcio-Bezerra ML, Abrahao A, Nunes KF, de Oliveira Braga NI, Oliveira ASB, Zinman L, Manzano GM (2018) Motor unit number index and neurophysiological index as candidate biomarkers of presymptomatic motor neuron loss in amyotrophic lateral sclerosis. Muscle Nerve 58:204–212. CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

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

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