Cell therapy for ischemic stroke

Authors

DOI:

https://doi.org/10.25305/unj.209118

Keywords:

ischemic cascade, cell therapy, stem cells, stem cells delivery, clinical trials

Abstract

Stroke is the second, and in some countries the third cause of mortality in the population and one of the causes of disability in the adult population. According to statistics, in 2018, 15 million cases of stroke and 6 million deaths were diagnosed,

The only currently approved treatments for acute stroke are intravenous tissue plasminogen activator (rtPA) and intra-arterial thrombectomy, which are used in less than 10% and 1% of patients, respectively.

The literature review is devoted to the pathophysiology and molecular mechanisms of damage in cerebral ischemia. The modern concept of two strategies of cell therapy is discussed: neuroprotection and remodeling; the role of stem cells in reducing local and systemic inflammation, neurogenesis and angiogenesis, increasing neuronal plasticity, and protecting the blood-brain barrier, the role of paracrine factors and extracellular vesicles is shown.

Methods of stem cell delivery are described: direct intracerebral transplantation, intraventricular and intrathecal, intravenous and intraarterial; the number of cells, their type and optimal delivery time depending on the acute, subacute and chronic periods of stroke. We also described recently designed the radially branched deployment (RBD) device and Cleveland multiport catheter for convection-enhanced delivery in which a cell-delivery catheter can be deployed at various angles and depths from a single longitudinal cannula. Finally, data on the completed 15 clinical trials from 2015 to the present, in which 513 patients took part, are presented. A detailed analysis of the efficacy and safety of cell therapy has been carried out.

Author Biographies

Vyacheslav S. Botev, Ivano-Frankivsk National Medical University

Department of Neurology and Neurosurgery

Viktoria A. Gryb, Ivano-Frankivsk National Medical University

Department of Neurology and Neurosurgery

References

1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 Mar 3;141(9):e139-e596. [CrossRef] [PubMed]

2. Global stroke fact sheet – World Stroke Organization, 2020. https://www.world-stroke.org/assets/downloads/WSO_Global_Stroke_Fact_Sheet.pdf

3. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, Ahmed M, Aksut B, Alam T, Alam K, Alla F, Alvis-Guzman N, Amrock S, Ansari H, Ärnlöv J, Asayesh H, Atey TM, Avila-Burgos L, Awasthi A, Banerjee A, Barac A, Bärnighausen T, Barregard L, Bedi N, Belay Ketema E, Bennett D, Berhe G, Bhutta Z, Bitew S, Carapetis J, Carrero JJ, Malta DC, Castañeda-Orjuela CA, Castillo-Rivas J, Catalá-López F, Choi JY, Christensen H, Cirillo M, Cooper L Jr, Criqui M, Cundiff D, Damasceno A, Dandona L, Dandona R, Davletov K, Dharmaratne S, Dorairaj P, Dubey M, Ehrenkranz R, El Sayed Zaki M, Faraon EJA, Esteghamati A, Farid T, Farvid M, Feigin V, Ding EL, Fowkes G, Gebrehiwot T, Gillum R, Gold A, Gona P, Gupta R, Habtewold TD, Hafezi-Nejad N, Hailu T, Hailu GB, Hankey G, Hassen HY, Abate KH, Havmoeller R, Hay SI, Horino M, Hotez PJ, Jacobsen K, James S, Javanbakht M, Jeemon P, John D, Jonas J, Kalkonde Y, Karimkhani C, Kasaeian A, Khader Y, Khan A, Khang YH, Khera S, Khoja AT, Khubchandani J, Kim D, Kolte D, Kosen S, Krohn KJ, Kumar GA, Kwan GF, Lal DK, Larsson A, Linn S, Lopez A, Lotufo PA, El Razek HMA, Malekzadeh R, Mazidi M, Meier T, Meles KG, Mensah G, Meretoja A, Mezgebe H, Miller T, Mirrakhimov E, Mohammed S, Moran AE, Musa KI, Narula J, Neal B, Ngalesoni F, Nguyen G, Obermeyer CM, Owolabi M, Patton G, Pedro J, Qato D, Qorbani M, Rahimi K, Rai RK, Rawaf S, Ribeiro A, Safiri S, Salomon JA, Santos I, Santric Milicevic M, Sartorius B, Schutte A, Sepanlou S, Shaikh MA, Shin MJ, Shishehbor M, Shore H, Silva DAS, Sobngwi E, Stranges S, Swaminathan S, Tabarés-Seisdedos R, Tadele Atnafu N, Tesfay F, Thakur JS, Thrift A, Topor-Madry R, Truelsen T, Tyrovolas S, Ukwaja KN, Uthman O, Vasankari T, Vlassov V, Vollset SE, Wakayo T, Watkins D, Weintraub R, Werdecker A, Westerman R, Wiysonge CS, Wolfe C, Workicho A, Xu G, Yano Y, Yip P, Yonemoto N, Younis M, Yu C, Vos T, Naghavi M, Murray C. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017 Jul 4;70(1):1-25. [CrossRef] [PubMed] [PubMed Central]

4. Kravets OV. [Structure of Rendering Emergency and Early Hospital Procedures in Acute Vascular Events]. Coliection of scientific works of staff member of P. L. Shupyk NMAPE. 2014;(23(2)):219-26. Ukrainian. http://nbuv.gov.ua/UJRN/Znpsnmapo_2014_23(2)__32

5. Saver JL. Time is brain--quantified. Stroke. 2006 Jan;37(1):263-6. [CrossRef] [PubMed]

6. Desai SM, Rocha M, Jovin TG, Jadhav AP. High Variability in Neuronal Loss. Stroke. 2019 Jan;50(1):34-37. [CrossRef] [PubMed]

7. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991-1045. [CrossRef] [PubMed]

8. Gülke E, Gelderblom M, Magnus T. Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Disord. 2018 May 22;11:1756286418774254. [CrossRef] [PubMed] [PubMed Central]

9. Roh JS, Sohn DH. Damage-Associated Molecular Patterns in Inflammatory Diseases. Immune Netw. 2018 Aug 13;18(4):e27. [CrossRef] [PubMed] [PubMed Central]

10. Chavez JC, Hurko O, Barone FC, Feuerstein GZ. Pharmacologic interventions for stroke: looking beyond the thrombolysis time window into the penumbra with biomarkers, not a stopwatch. Stroke. 2009 Oct;40(10):e558-63. [CrossRef] [PubMed]

11. Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, Cheripelli B, Cho TH, Fazekas F, Fiehler J, Ford I, Galinovic I, Gellissen S, Golsari A, Gregori J, Günther M, Guibernau J, Häusler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, Neeb L, Perez de la Ossa N, Puig J, Ringleb P, Roy P, Scheel E, Schonewille W, Serena J, Sunaert S, Villringer K, Wouters A, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C; WAKE-UP Investigators. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7):611-622. [CrossRef] [PubMed]

12. Lisianyi MI. [Cell therapy in experimental TBI]. Ukrainian Neurosurgical Journal. 2020;26(2):5-13. Ukrainian. [CrossRef]

13. Houkin K, Abe K, Kuroda S, editors. Cell Therapy Against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials. Tokyo: Springer; 2017. [CrossRef]

14. Boshuizen MCS, Steinberg GK. Stem Cell-Based Immunomodulation After Stroke: Effects on Brain Repair Processes. Stroke. 2018 Jun;49(6):1563-1570. [CrossRef] [PubMed] [PubMed Central]

15. Dabrowska S, Andrzejewska A, Lukomska B, Janowski M. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation. 2019 Sep 12;16(1):178. [CrossRef] [PubMed] [PubMed Central]

16. Tobin MK, Stephen TKL, Lopez KL, Pergande MR, Bartholomew AM, Cologna SM, Lazarov O. Activated Mesenchymal Stem Cells Induce Recovery Following Stroke Via Regulation of Inflammation and Oligodendrogenesis. J Am Heart Assoc. 2020 Apr 7;9(7):e013583. [CrossRef] [PubMed] [PubMed Central]

17. Xu W, Zheng J, Gao L, Li T, Zhang J, Shao A. Neuroprotective Effects of Stem Cells in Ischemic Stroke. Stem Cells Int. 2017;2017:4653936. [CrossRef] [PubMed] [PubMed Central]

18. Benedek A, Cernica D, Mester A, Opincariu D, Hodas R, Rodean I, Keri J, Benedek T. Modern Concepts in Regenerative Therapy for Ischemic Stroke: From Stem Cells for Promoting Angiogenesis to 3D-Bioprinted Scaffolds Customized via Carotid Shear Stress Analysis. Int J Mol Sci. 2019 May 25;20(10):2574. [CrossRef] [PubMed] [PubMed Central]

19. Koh SH, Park HH. Neurogenesis in Stroke Recovery. Transl Stroke Res. 2017 Feb;8(1):3-13. [CrossRef] [PubMed]

20. Lu J, Manaenko A, Hu Q. Targeting Adult Neurogenesis for Poststroke Therapy. Stem Cells Int. 2017;2017:5868632. [CrossRef] [PubMed] [PubMed Central]

21. Horie N, Hiu T, Nagata I. Stem cell transplantation enhances endogenous brain repair after experimental stroke. Neurol Med Chir (Tokyo). 2015;55(2):107-12. [CrossRef] [PubMed] [PubMed Central]

22. Ottoboni L, von Wunster B, Martino G. Therapeutic Plasticity of Neural Stem Cells. Front Neurol. 2020 Mar 20;11:148. [CrossRef] [PubMed] [PubMed Central]

23. Zhang W, Zhu L, An C, Wang R, Yang L, Yu W, Li P, Gao Y. The blood brain barrier in cerebral ischemic injury–Disruption and repair. Brain Hemorrhages. 2020 Mar 1;1(1):34-53. [CrossRef]

24. Bang OY, Kim EH. Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy for Stroke: Challenges and Progress. Front Neurol. 2019 Mar 12;10:211. [CrossRef] [PubMed] [PubMed Central]

25. Doeppner TR, Bähr M, Giebel B, Hermann DM. Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain. Ther Adv Neurol Disord. 2018 Jul 26;11:1756286418789326. [CrossRef] [PubMed] [PubMed Central]

26. Tian T, Zhang HX, He CP, Fan S, Zhu YL, Qi C, Huang NP, Xiao ZD, Lu ZH, Tannous BA, Gao J. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials. 2018 Jan;150:137-149. [CrossRef] [PubMed]

27. Phinney DG, Pittenger MF. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells. 2017 Apr;35(4):851-858. [CrossRef] Erratum in: Stem Cells. 2017 Sep;35(9):2103. [PubMed]

28. Zhu Z, Kalyan BS, Chen L. Therapeutic potential role of exosomes for ischemic stroke. Brain Science Advances. 2019 Jun;5(2):128-43. [CrossRef]

29. Li Y, Cheng Q, Hu G, Deng T, Wang Q, Zhou J, Su X. Extracellular vesicles in mesenchymal stromal cells: A novel therapeutic strategy for stroke. Exp Ther Med. 2018 May;15(5):4067-4079. [CrossRef] [PubMed] [PubMed Central]

30. Kalladka D, Sinden J, Pollock K, Haig C, McLean J, Smith W, McConnachie A, Santosh C, Bath PM, Dunn L, Muir KW. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet. 2016 Aug 20;388(10046):787-96. [CrossRef] [PubMed]

31. Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, Kim AS, Johnson JN, Bates D, King B, Case C, McGrogan M, Yankee EW, Schwartz NE. Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke. 2016 Jul;47(7):1817-24. [CrossRef] [PubMed] [PubMed Central]

32. Zhang GL, Zhu ZH, Wang YZ. Neural stem cell transplantation therapy for brain ischemic stroke: Review and perspectives. World J Stem Cells. 2019 Oct 26;11(10):817-830. [CrossRef] [PubMed] [PubMed Central]

33. Muir KW, Bulters D, Willmot M, Sprigg N, Dixit A, Ward N, Tyrrell P, Majid A, Dunn L, Bath P, Howell J, Stroemer P, Pollock K, Sinden J. Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2). J Neurol Neurosurg Psychiatry. 2020 Apr;91(4):396-401. [CrossRef] [PubMed] [PubMed Central]

34. Jin Y, Ying L, Yu G, Nan G. Analysis of the long-term effect of bone marrow mononuclear cell transplantation for the treatment of cerebral infarction. International Journal of Clinical and Experimental Medicine. 2017 Jan 1;10(2):3059-68. https://api.semanticscholar.org/CorpusID:197463836

35. Taguchi A, Sakai C, Soma T, Kasahara Y, Stern DM, Kajimoto K, Ihara M, Daimon T, Yamahara K, Doi K, Kohara N, Nishimura H, Matsuyama T, Naritomi H, Sakai N, Nagatsuka K. Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients. Stem Cells Dev. 2015 Oct 1;24(19):2207-18. [CrossRef] [PubMed] [PubMed Central]

36. Hess DC, Wechsler LR, Clark WM, Savitz SI, Ford GA, Chiu D, Yavagal DR, Uchino K, Liebeskind DS, Auchus AP, Sen S, Sila CA, Vest JD, Mays RW. 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 May;16(5):360-368. [CrossRef] [PubMed]

37. Bhasin A, Kumaran SS, Bhatia R, Mohanty S, Srivastava MVP. Safety and Feasibility of Autologous Mesenchymal Stem Cell Transplantation in Chronic Stroke in Indian patients. A four-year follow up. J Stem Cells Regen Med. 2017 May 30;13(1):14-19. [CrossRef] [PubMed] [PubMed Central]

38. Laskowitz DT, Bennett ER, Durham RJ, Volpi JJ, Wiese JR, Frankel M, Shpall E, Wilson JM, Troy J, Kurtzberg J. Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase I Safety Study. Stem Cells Transl Med. 2018 Jul;7(7):521-529. [CrossRef] [PubMed] [PubMed Central]

39. Fang J, Guo Y, Tan S, Li Z, Xie H, Chen P, Wang K, He Z, He P, Ke Y, Jiang X, Chen Z. Autologous Endothelial Progenitor Cells Transplantation for Acute Ischemic Stroke: A 4-Year Follow-Up Study. Stem Cells Transl Med. 2019 Jan;8(1):14-21. [CrossRef] [PubMed] [PubMed Central]

40. Levy ML, Crawford JR, Dib N, Verkh L, Tankovich N, Cramer SC. Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke. Stroke. 2019 Oct;50(10):2835-2841. [CrossRef] [PubMed]

41. Jaillard A, Hommel M, Moisan A, Zeffiro TA, Favre-Wiki IM, Barbieux-Guillot M, Vadot W, Marcel S, Lamalle L, Grand S, Detante O; (for the ISIS-HERMES Study Group). Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial. Transl Stroke Res. 2020 Oct;11(5):910-923. [CrossRef] [PubMed]

42. Ghali AA, Yousef MK, Ragab OA, ElZamarany EA. Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Stem Cells in Subacute Ischemic Stroke Patients. Front Neurol. 2016 Dec 16;7:228. [CrossRef] [PubMed] [PubMed Central]

43. Bhatia V, Gupta V, Khurana D, Sharma RR, Khandelwal N. Randomized Assessment of the Safety and Efficacy of Intra-Arterial Infusion of Autologous Stem Cells in Subacute Ischemic Stroke. AJNR Am J Neuroradiol. 2018 May;39(5):899-904. [CrossRef] [PubMed] [PubMed Central]

44. Savitz SI, Yavagal D, Rappard G, Likosky W, Rutledge N, Graffagnino C, Alderazi Y, Elder JA, Chen PR, Budzik RF Jr, Tarrel R, Huang DY, Hinson JM Jr. 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 Jan 8;139(2):192-205. [CrossRef] [PubMed]

45. Liu H, Honmou O, Harada K, Nakamura K, Houkin K, Hamada H, Kocsis JD. Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain. 2006 Oct;129(Pt 10):2734-45. [CrossRef] [PubMed] [PubMed Central]

46. Guzman R, Janowski M, Walczak P. Intra-Arterial Delivery of Cell Therapies for Stroke. Stroke. 2018 May;49(5):1075-1082. [CrossRef] [PubMed] [PubMed Central]

47. Baker EW, Kinder HA, West FD. Neural stem cell therapy for stroke: A multimechanistic approach to restoring neurological function. Brain Behav. 2019 Mar;9(3):e01214. [CrossRef] [PubMed] [PubMed Central]

48. Martínez-Garza DM, Cantú-Rodríguez OG, Jaime-Pérez JC, Gutiérrez-Aguirre CH, Góngora-Rivera JF, Gómez-Almaguer D. Current state and perspectives of stem cell therapy for stroke. Medicina Universitaria. 2016 Jul 1;18(72):169-80. [CrossRef]

49. Rosado-de-Castro PH, Schmidt Fda R, Battistella V, Lopes de Souza SA, Gutfilen B, Goldenberg RC, Kasai-Brunswick TH, Vairo L, Silva RM, Wajnberg E, Alvarenga Americano do Brasil PE, Gasparetto EL, Maiolino A, Alves-Leon SV, Andre C, Mendez-Otero R, Rodriguez de Freitas G, Barbosa da Fonseca LM. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen Med. 2013 Mar;8(2):145-55. [CrossRef] [PubMed]

50. Manley NC, Azevedo-Pereira RL, Bliss TM, Steinberg GK. Neural stem cells in stroke: Intracerebral approaches. In: Hess D., editor. Cell therapy for brain injury Springer; 2015. P. 91-109. [CrossRef]

51. Martin AJ, Starr PA, Ostrem JL, Larson PS. Hemorrhage Detection and Incidence during Magnetic Resonance-Guided Deep Brain Stimulator Implantations. Stereotact Funct Neurosurg. 2017;95(5):307-314. [CrossRef] [PubMed]

52. Winkler EA, Lim DA. Stem Cell Transplantation for Neurological Disease: Technical Considerations and Delivery Devices. In: Lonser RR, Sarntinoranont M, Bankiewicz K, editors. Nervous System Drug Delivery: Principles and Practice. Academic Press; 2019. P. 351-364. [CrossRef]

53. Kondziolka D, Steinberg GK, Cullen SB, McGrogan M. Evaluation of surgical techniques for neuronal cell transplantation used in patients with stroke. Cell Transplant. 2004;13(7-8):749-54. [CrossRef] [PubMed]

54. Kawabori M, Tanimori A, Kitta S, Shichinohe H, Houkin K. Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease. Stem Cells Int. 2020 Feb 11;2020:4085617. [CrossRef] [PubMed] [PubMed Central]

55. Silvestrini MT, Yin D, Coppes VG, Mann P, Martin AJ, Larson PS, Starr PA, Gupta N, Panter SS, Desai TA, Lim DA. Radially branched deployment for more efficient cell transplantation at the scale of the human brain. Stereotact Funct Neurosurg. 2013;91(2):92-103. [CrossRef] [PubMed] [PubMed Central]

56. Vogelbaum MA, Brewer C, Barnett GH, Mohammadi AM, Peereboom DM, Ahluwalia MS, Gao S. First-in-human evaluation of the Cleveland Multiport Catheter for convection-enhanced delivery of topotecan in recurrent high-grade glioma: results of pilot trial 1. J Neurosurg. 2018 Apr 1:1-10. [CrossRef] [PubMed]

57. Krause M, Phan TG, Ma H, Sobey CG, Lim R. Cell-Based Therapies for Stroke: Are We There Yet? Front Neurol. 2019 Jun 25;10:656. [CrossRef] [PubMed] [PubMed Central]

Published

2020-12-08

Issue

Section

Review articles