Advertisement

Stem Cell Reviews and Reports

, Volume 15, Issue 2, pp 176–193 | Cite as

Cell Therapy for Ischemic Stroke: How to Turn a Promising Preclinical Research into a Successful Clinical Story

  • Gabrielle Mangin
  • Nathalie KubisEmail author
Article

Abstract

Stroke is a major public health issue with limited treatment. The pharmacologically or mechanically removing of the clot is accessible to less than 10% of the patients. Stem cell therapy is a promising alternative strategy since it increases the therapeutic time window but many issues remain unsolved. To avoid a new dramatic failure when translating experimental data on the bedside, this review aims to highlight the indispensable checkpoints to make a successful clinical trial based on the current preclinical literature. The large panel of progenitors/ stem cells at the researcher’s disposal is to be used wisely, regarding the type of cells, the source of cells, the route of delivery, the time window, since it will directly affect the outcome. Mechanisms are still incompletely understood, although recent studies have focused on the inflammation modulation of most cells types.

Keywords

Stem cells Progenitors Brain ischemia Cerebrovascular disease Immunomodulation 

Abbreviations

AD-MSC

adipose mesenchymal stem cell

BBB

blood brain barrier

BM

bone marrow

CB

cord blood

ECFC

endothelial colony forming cell

EPC

endothelial progenitor cell

ESC

embryonic stem cell

hUCB

human umbilical cord blood

HSC

hematopoietic stem cell

IA

intraarterial

IC

intracerebral

iPSC

induced pluripotent stem cell

IV

intravenous

MAC

myeloid angiogenic cell

MAPC

multipotent adult progenitor cell

miR

micro-RNA

MSC

mesenchymal stem cell

MNC

mononuclear cells

NPC

neural progenitor cell

NSC

neural stem cell

PB

peripheral blood

pMCAo

permanent middle cerebral artery occlusion

SMPC

smooth muscle progenitor cell

SVZ

subventricular zone

tMCAo

transient middle cerebral artery occlusion

Notes

Acknowledgements

GM was funded by the RESSTORE project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 681044 RESSTORE project (www.resstore.eu). The authors wish to thank the site smart.servier.fr for their image bank, which was used in part for the graphical illustration.

Compliance with Ethical Standards

Conflict of Interests

The authors have declared that no competing interest exists.

References

  1. 1.
    Organization WH. The top 10 causes of death. http://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. Accessed 24 May 2018.
  2. 2.
    Organisation WH. Priority Medicines for Europe and the World 2013 Update. http://www.who.int/medicines/areas/priority_medicines/MasterDocJune28_FINAL_Web.pdf. Accessed 9 July 2013.
  3. 3.
    Spieler, J. F., Lanoe, J. L., & Amarenco, P. (2004). Costs of stroke care according to handicap levels and stroke subtypes. Cerebrovascular Diseases, 17(2–3), 134–142.Google Scholar
  4. 4.
    Mathers, C. D., & Loncar, D. (2006). Projections of global mortality and burden of disease from 2002 to 2030. PLoS Medicine, 3, e442.Google Scholar
  5. 5.
    Kuklina, E. V., Tong, X., George, M. G., & Bansil, P. (2012). Epidemiology and prevention of stroke: A worldwide perspective. Expert Review of Neurotherapeutics, 12, 199–208.Google Scholar
  6. 6.
    Snyder, H. M., Corriveau, R. A., Craft, S., Faber, J. E., Greenberg, S. M., Knopman, D., Lamb, B. T., Montine, T. J., Nedergaard, M., Schaffer, C. B., Schneider, J. A., Wellington, C., Wilcock, D. M., Zipfel, G. J., Zlokovic, B., Bain, L. J., Bosetti, F., Galis, Z. S., Koroshetz, W., & Carrillo, M. C. (2015). Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement, 11(6), 710–717.Google Scholar
  7. 7.
    Jovin, T. G., Chamorro, A., Cobo, E., de Miquel, M. A., Molina, C. A., Rovira, A., San Román, L., Serena, J., Abilleira, S., Ribó, M., Millán, M., Urra, X., Cardona, P., López-Cancio, E., Tomasello, A., Castaño, C., Blasco, J., Aja, L., Dorado, L., Quesada, H., Rubiera, M., Hernandez-Pérez, M., Goyal, M., Demchuk, A. M., von Kummer, R., Gallofré, M., Dávalos, A., & REVASCAT Trial Investigators. (2015). Thrombectomy within 8 hours after symptom onset in ischemic stroke. The New England Journal of Medicine, 372, 2296–2306.Google Scholar
  8. 8.
    Jean LeBlanc, N., Guruswamy, R., & ElAli, A. (2018). Vascular endothelial growth factor isoform-B stimulates neurovascular repair after ischemic stroke by promoting the function of Pericytes via vascular endothelial growth factor Receptor-1. Molecular Neurobiology, 55(5), 3611–3626.Google Scholar
  9. 9.
    Ekdahl, C. T., Kokaia, Z., & Lindvall, O. (2009). Brain inflammation and adult neurogenesis: The dual role of microglia. Neuroscience, 158, 1021–1029.Google Scholar
  10. 10.
    Nih, L. R., Deroide, N., Leré-Déan, C., Lerouet, D., Soustrat, M., Levy, B. I., Silvestre, J. S., Merkulova-Rainon, T., Pocard, M., Margaill, I., & Kubis, N. (2012). Neuroblast survival depends on mature vascular network formation after mouse stroke: Role of endothelial and smooth muscle progenitor cell co-administration. European Journal of Neuroscience, 35, 1208–1217.Google Scholar
  11. 11.
    Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., Martino, G., & Schwartz, M. (2006). Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Molecular and Cellular Neurosciences, 31, 149–160.Google Scholar
  12. 12.
    Cramer, S. C., & Chopp, M. (2000). Recovery recapitulates ontogeny. Trends in Neurosciences, 23, 265–271.Google Scholar
  13. 13.
    Detante, O., Moisan, A., Hommel, M., & Jaillard, A. (2017). Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment. International Journal of Stroke, 12(7), 748–751.Google Scholar
  14. 14.
    Viner Smith, E., Tierney, A. C., Klarica, D., Walker, P., & Avery, S. (2016). Impact of a lifestyle modification program on the metabolic syndrome and associated risk factors in long-term survivors of stem cell transplantation. Bone Marrow Transplantation, 51(5), 722–724.Google Scholar
  15. 15.
    Detante, O., Jaillard, A., Moisan, A., Barbieux, M., Favre, I. M., Garambois, K., Hommel, M., & Remy, C. (2014). Biotherapies in stroke. Revue Neurologique, 170, 779–798.Google Scholar
  16. 16.
    Mergenthaler, P., & Meisel, A. (2012). Do stroke models model stroke? Disease Models & Mechanisms, 5, 718–725.Google Scholar
  17. 17.
    Participants SCTaaEPiS. (2009). Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): Bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke, 40, 510–515.Google Scholar
  18. 18.
    Chu, K., Kim, M., Park, K.-I., Jeong, S.-W., Park, H.-K., Jung, K.-H., Lee, S. T., Kang, L., Lee, K., Park, D. K., Kim, S. U., & Roh, J. K. (2004). Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Research, 1016, 145–153.Google Scholar
  19. 19.
    Ishibashi, S., Sakaguchi, M., Kuroiwa, T., Yamasaki, M., Kanemura, Y., Shizuko, I., Shimazaki, T., Onodera, M., Okano, H., & Mizusawa, H. (2004). Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils. Journal of Neuroscience Research, 78, 215–223.Google Scholar
  20. 20.
    Jiang, Q., Zhang, Z. G., Ding, G. L., Zhang, L., Ewing, J. R., Wang, L., Zhang, R. L., Li, L., Lu, M., Meng, H., Arbab, A. S., Hu, J., Li, Q. J., Pourabdollah Nejad D, S., Athiraman, H., & Chopp, M. (2005). Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI. NeuroImage, 28, 698–707.Google Scholar
  21. 21.
    Savitz, S. I., Dinsmore, J., Wu, J., Henderson, G. V., Stieg, P., & Caplan, L. R. (2005). Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: A preliminary safety and feasibility study. Cerebrovascular Diseases (Basel, Switzerland), 20, 101–107.Google Scholar
  22. 22.
    Borlongan, C. V., Tajima, Y., Trojanowski, J. Q., Lee, V. M., & Sanberg, P. R. (1998). Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Experimental Neurology, 149, 310–321.Google Scholar
  23. 23.
    Kondziolka, D., Wechsler, L., Goldstein, S., Meltzer, C., Thulborn, K. R., Gebel, J., Jannetta, P., DeCesare, S., Elder, E. M., McGrogan, M., Reitman, M. A., & Bynum, L. (2000). Transplantation of cultured human neuronal cells for patients with stroke. Neurology, 55, 565–569.Google Scholar
  24. 24.
    Bain, G., Kitchens, D., Yao, M., Huettner, J. E., & Gottlieb, D. I. (1995). Embryonic stem cells express neuronal properties in vitro. Developmental Biology, 168, 342–357.Google Scholar
  25. 25.
    Okabe, S., Forsberg-Nilsson, K., Spiro, A. C., Segal, M., & McKay, R. D. (1996). Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mechanisms of Development, 59, 89–102.Google Scholar
  26. 26.
    Reubinoff, B. E., Itsykson, P., Turetsky, T., Pera, M. F., Reinhartz, E., Itzik, A., & Ben-Hur, T. (2001). Neural progenitors from human embryonic stem cells. Nature Biotechnology, 19, 1134–1140.Google Scholar
  27. 27.
    Ying, Q.-L., Stavridis, M., Griffiths, D., Li, M., & Smith, A. (2003). Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nature Biotechnology, 21, 183–186.Google Scholar
  28. 28.
    Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O., & Thomson, J. A. (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nature Biotechnology, 19(12), 1129–1133.Google Scholar
  29. 29.
    Bühnemann, C., Scholz, A., Bernreuther, C., Malik, C. Y., Braun, H., Schachner, M., et al. (2006). Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain: A Journal of Neurology, 129, 3238–3248.Google Scholar
  30. 30.
    Daadi, M. M., Maag, A.-L., & Steinberg, G. K. (2008). Adherent self-renewable human embryonic stem cell-derived neural stem cell line: Functional engraftment in experimental stroke model. PLoS One, 3, e1644.Google Scholar
  31. 31.
    Hayashi, J., Takagi, Y., Fukuda, H., Imazato, T., Nishimura, M., Fujimoto, M., Takahashi, J., Hashimoto, N., & Nozaki, K. (2006). Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 26, 906–914.Google Scholar
  32. 32.
    Hicks, A. U., Lappalainen, R. S., Narkilahti, S., Suuronen, R., Corbett, D., Sivenius, J., Hovatta, O., & Jolkkonen, J. (2009). Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: Cell survival and functional recovery. The European Journal of Neuroscience, 29, 562–574.Google Scholar
  33. 33.
    Kim, D.-Y., Park, S.-H., Lee, S.-U., Choi, D.-H., Park, H.-W., Paek, S. H., Shin, H. Y., Kim, E. Y., Park, S. P., & Lim, J. H. (2007). Effect of human embryonic stem cell-derived neuronal precursor cell transplantation into the cerebral infarct model of rat with exercise. Neuroscience Research, 58, 164–175.Google Scholar
  34. 34.
    Seminatore, C., Polentes, J., Ellman, D., Kozubenko, N., Itier, V., Tine, S., Tritschler, L., Brenot, M., Guidou, E., Blondeau, J., Lhuillier, M., Bugi, A., Aubry, L., Jendelova, P., Sykova, E., Perrier, A. L., Finsen, B., & Onteniente, B. (2010). The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke, 41, 153–159.Google Scholar
  35. 35.
    Harper, J. C., Geraedts, J., Borry, P., Cornel, M. C., Dondorp, W., Gianaroli, L., Harton, G., Milachich, T., Kääriäinen, H., Liebaers, I., Morris, M., Sequeiros, J., Sermon, K., Shenfield, F., Skirton, H., Soini, S., Spits, C., Veiga, A., Vermeesch, J. R., Viville, S., de Wert, G., Macek M Jr, ESHG, ESHRE, & EuroGentest2. (2013). Current issues in medically assisted reproduction and genetics in Europe: Research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology. European Journal of Human Genetics: EJHG, 21(Suppl 2), S1–21.Google Scholar
  36. 36.
    Xiao, X., Li, N., Zhang, D., Yang, B., Guo, H., & Li, Y. (2016). Generation of induced pluripotent stem cells with substitutes for Yamanaka's four transcription factors. Cellular Reprogramming, 18, 281–297.Google Scholar
  37. 37.
    Kawai, H., Yamashita, T., Ohta, Y., Deguchi, K., Nagotani, S., Zhang, X., Ikeda, Y., Matsuura, T., & Abe, K. (2010). Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. Journal of Cerebral Blood Flow and Metabolism, 30(8), 1487–1493.Google Scholar
  38. 38.
    Oki, K., Tatarishvili, J., Wood, J., Koch, P., Wattananit, S., Mine, Y., Monni, E., Tornero, D., Ahlenius, H., Ladewig, J., Brüstle, O., Lindvall, O., & Kokaia, Z. (2012). Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells (Dayton, Ohio), 30, 1120–1133.Google Scholar
  39. 39.
    Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., & Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology, 26, 101–106.Google Scholar
  40. 40.
    Wernig, M., Meissner, A., Cassady, J. P., & Jaenisch, R. (2008). c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell, 2, 10–12.Google Scholar
  41. 41.
    Mohamad, O., Drury-Stewart, D., Song, M., Faulkner, B., Chen, D., Yu, S. P., & Wei, L. (2013). Vector-free and transgene-free human iPS cells differentiate into functional neurons and enhance functional recovery after ischemic stroke in mice. PLoS One, 8, e64160.Google Scholar
  42. 42.
    Nishimura, K., Ohtaka, M., Takada, H., Kurisaki, A., Tran, N. V. K., Tran, Y. T. H., Hisatake, K., Sano, M., & Nakanishi, M. (2017). Simple and effective generation of transgene-free induced pluripotent stem cells using an auto-erasable Sendai virus vector responding to microRNA-302. Stem Cell Research, 23, 13–19.Google Scholar
  43. 43.
    Medina, R. J., Barber, C. L., Sabatier, F., Dignat-George, F., Melero-Martin, J. M., Khosrotehrani, K., Ohneda, O., Randi, A. M., Chan, J. K. Y., Yamaguchi, T., van Hinsbergh, V. W. M., Yoder, M. C., & Stitt, A. W. (2017). Endothelial progenitors: A consensus statement on nomenclature. Stem Cells Translational Medicine, 6(5), 1316–1320.Google Scholar
  44. 44.
    Fan, Y., Shen, F., Frenzel, T., Zhu, W., Ye, J., Liu, J., Chen, Y., Su, H., Young, W. L., & Yang, G. Y. (2010). Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Annals of Neurology, 67(4), 488–497.Google Scholar
  45. 45.
    Chen, Z.-Z., Jiang, X.-D., Zhang, L.-L., Shang, J.-H., Du, M.-X., Xu, G., et al. (2008). Beneficial effect of autologous transplantation of bone marrow stromal cells and endothelial progenitor cells on cerebral ischemia in rabbits. Neuroscience Letters, 445, 36–41.Google Scholar
  46. 46.
    George, J., Afek, A., Abashidze, A., Shmilovich, H., Deutsch, V., Kopolovich, J., Miller, H., & Keren, G. (2005). Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 2636–2641.Google Scholar
  47. 47.
    Poittevin, M., Lozeron, P., Hilal, R., Levy, B. I., Merkulova-Rainon, T., & Kubis, N. (2013). Smooth muscle cell phenotypic switching in stroke. Translational Stroke Research, 5(3), 377–84.Google Scholar
  48. 48.
    Guerin, C. L., Loyer, X., Vilar, J., Cras, A., Mirault, T., Gaussem, P., Silvestre, J. S., & Smadja, D. M. (2015). Bone-marrow-derived very small embryonic-like stem cells in patients with critical leg ischaemia: Evidence of vasculogenic potential. Thrombosis and Haemostasis, 113, 1084–1094.Google Scholar
  49. 49.
    Ratajczak, M. Z., Zuba-Surma, E. K., Machalinski, B., Ratajczak, J., & Kucia, M. (2008). Very small embryonic-like (VSEL) stem cells: Purification from adult organs, characterization, and biological significance. Stem Cell Reviews, 4(2), 89–99.Google Scholar
  50. 50.
    Ratajczak, J., Zuba-Surma, E., Paczkowska, E., Kucia, M., Nowacki, P., & Ratajczak, M. Z. (2011). Stem cells for neural regeneration--a potential application of very small embryonic-like stem cells. Journal of Physiology and Pharmacology, 62(1), 3–12.Google Scholar
  51. 51.
    Schwarting, S., Litwak, S., Hao, W., Bahr, M., Weise, J., & Neumann, H. (2008). Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke, 39(10), 2867–2875.Google Scholar
  52. 52.
    Esquiva, G., Grayston, A., & Revascularization, R. A. (2018). Endothelial progenitor cells in stroke. American Journal of Physiology. Cell Physiology, 315, C664–C674.Google Scholar
  53. 53.
    Moubarik, C., Guillet, B., Youssef, B., Codaccioni, J. L., Piercecchi, M. D., Sabatier, F., Lionel, P., Dou, L., Foucault-Bertaud, A., Velly, L., Dignat-George, F., & Pisano, P. (2011). Transplanted late outgrowth endothelial progenitor cells as cell therapy product for stroke. Stem Cell Reviews, 7(1), 208–220.Google Scholar
  54. 54.
    Alexander, M. R., & Owens, G. K. (2012). Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annual Review of Physiology, 74, 13–40.Google Scholar
  55. 55.
    Rodgerson, D. O., & Harris, A. G. (2011). A comparison of stem cells for therapeutic use. Stem Cell Reviews, 7(4), 782–796.Google Scholar
  56. 56.
    Buhring, H. J., Battula, V. L., Treml, S., Schewe, B., Kanz, L., & Vogel, W. (2007). Novel markers for the prospective isolation of human MSC. Annals of the New York Academy of Sciences, 1106, 262–271.Google Scholar
  57. 57.
    Hao, L., Zou, Z., Tian, H., Zhang, Y., Zhou, H., & Liu, L. (2014). Stem cell-based therapies for ischemic stroke. BioMed Research International, 2014, 1–17.Google Scholar
  58. 58.
    Ratajczak, M. Z., Zuba-Surma, E. K., Wojakowski, W., Ratajczak, J., & Kucia, M. (2008). Bone marrow - home of versatile stem cells. Transfusion Medicine and Hemotherapy, 35(3), 248–259.Google Scholar
  59. 59.
    Mora-Lee, S., Sirerol-Piquer, M. S., Gutierrez-Perez, M., Gomez-Pinedo, U., Roobrouck, V. D., Lopez, T., et al. (2012). Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice. PLoS One, 7(8), e43683.Google Scholar
  60. 60.
    Yang, B., Hamilton, J. A., Valenzuela, K. S., Bogaerts, A., Xi, X., Aronowski, J., Mays, R. W., & Savitz, S. I. (2017). Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells, 35, 1290–1302.Google Scholar
  61. 61.
    Kassem, M. (2004). Mesenchymal stem cells: Biological characteristics and potential clinical applications. Cloning and Stem Cells, 6, 369–374.Google Scholar
  62. 62.
    Pontikoglou, C., Deschaseaux, F., Sensebé, L., & Papadaki, H. A. (2011). Bone marrow mesenchymal stem cells: Biological properties and their role in hematopoiesis and hematopoietic stem cell transplantation. Stem Cell Reviews, 7, 569–589.Google Scholar
  63. 63.
    Dharmasaroja, P. (2009). Bone marrow-derived mesenchymal stem cells for the treatment of ischemic stroke. Journal of Clinical Neuroscience, 16(1), 12–20.Google Scholar
  64. 64.
    Honmou, O., Onodera, R., Sasaki, M., Waxman, S. G., & Kocsis, J. D. (2012). Mesenchymal stem cells: Therapeutic outlook for stroke. Trends in Molecular Medicine, 18, 292–297.Google Scholar
  65. 65.
    Kalladka, D., & Muir, K. W. (2014). Brain repair: Cell therapy in stroke. Stem Cells and Cloning : Advances and Applications, 7, 31–44.Google Scholar
  66. 66.
    Sarmah, D., Agrawal, V., Rane, P., Bhute, S., Watanabe, M., Kalia, K., Ghosh, Z., Dave, K. R., Yavagal, D. R., & Bhattacharya, P. (2018). Mesenchymal stem cell therapy in ischemic stroke: A meta-analysis of preclinical studies. Clinical Pharmacology and Therapeutics, 103(6), 990–998.Google Scholar
  67. 67.
    Hossmann, K. A. (2012). The two pathophysiologies of focal brain ischemia: Implications for translational stroke research. Journal of Cerebral Blood Flow and Metabolism, 32(7), 1310–1316.Google Scholar
  68. 68.
    Tran-Dinh, A., Dinh, A. T., Kubis, N., Tomita, Y., Karaszewski, B., Calando, Y., et al. (2006). In vivo imaging with cellular resolution of bone marrow cells transplanted into the ischemic brain of a mouse. NeuroImage, 31, 958–967.Google Scholar
  69. 69.
    Chen, J., Li, Y., Wang, L., Lu, M., & Chopp, M. (2002). Caspase inhibition by Z-VAD increases the survival of grafted bone marrow cells and improves functional outcome after MCAo in rats. Journal of the Neurological Sciences, 199(1–2), 17–24.Google Scholar
  70. 70.
    Bang, O. Y., Lee, J. S., Lee, P. H., & Lee, G. (2005). Autologous mesenchymal stem cell transplantation in stroke patients. Annals of Neurology, 57, 874–882.Google Scholar
  71. 71.
    trials RaMaEc. RESSTORE REgenerative Stem cell therapy for STroke in Europe. https://clinicaltrials.gov/ct2/show/NCT03570450. Accessed 27 June 2018.
  72. 72.
    Rasmusson, I., Ringdén, O., Sundberg, B., & Le Blanc, K. (2005). Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Experimental Cell Research, 305, 33–41.Google Scholar
  73. 73.
    Ringdén, O., Uzunel, M., Rasmusson, I., Remberger, M., Sundberg, B., Lönnies, H., et al. (2006). Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation, 81, 1390–1397.Google Scholar
  74. 74.
    Lalu, M. M., McIntyre, L., Pugliese, C., Fergusson, D., Winston, B. W., Marshall, J. C., Granton, J., Stewart, D. J., & Canadian Critical Care Trials Group. (2012). Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta-analysis of clinical trials. PLoS One, 7, e47559.Google Scholar
  75. 75.
    Uccelli, A., Moretta, L., & Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nature Reviews. Immunology, 8(9), 726–736.Google Scholar
  76. 76.
    Ankrum, J. A., Ong, J. F., & Karp, J. M. (2014). Mesenchymal stem cells: immune evasive, not immune privileged. Nature Biotechnology, 32, 252–260.Google Scholar
  77. 77.
    Chen, J., Li, Y., Katakowski, M., Chen, X., Wang, L., Lu, D., Lu, M., Gautam, S. C., & Chopp, M. (2003). Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. Journal of Neuroscience Research, 73, 778–786.Google Scholar
  78. 78.
    Hess, D. C., Wechsler, L. R., Clark, W. M., Savitz, S. I., Ford, G. A., Chiu, D., Yavagal, D. R., Uchino, K., Liebeskind, D. S., Auchus, A. P., Sen, S., Sila, C. A., Vest, J. D., & Mays, R. W. (2017). Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. Neurology, 16, 360–368.Google Scholar
  79. 79.
    Brenneman, M., Sharma, S., Harting, M., Strong, R., Cox Jr., C. S., Aronowski, J., Grotta, J. C., & Savitz, S. I. (2010). Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. Journal of Cerebral Blood Flow and Metabolism, 30(1), 140–149.Google Scholar
  80. 80.
    Hilal, R., Poittevin, M., Pasteur-Rousseau, A., Cogo, A., Mangin, G., Chevauche, M., et al. (2018). Diabetic Ephrin-B2-stimulated peripheral blood mononuclear cells enhance poststroke recovery in mice. Stem Cells International, 2018, 2431567.Google Scholar
  81. 81.
    Barbosa da Fonseca, L. M., Gutfilen, B., Rosado de Castro, P. H., Battistella, V., Goldenberg, R. C., Kasai-Brunswick, T., et al. (2010). Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Experimental Neurology, 221(1), 122–128.Google Scholar
  82. 82.
    Battistella, V., de Freitas, G. R., da Fonseca, L. M., Mercante, D., Gutfilen, B., Goldenberg, R. C., et al. (2011). Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regenerative Medicine, 6(1), 45–52.Google Scholar
  83. 83.
    Bhasin, A., Srivastava, M., Bhatia, R., Mohanty, S., Kumaran, S., & Bose, S. (2012). Autologous intravenous mononuclear stem cell therapy in chronic ischemic stroke. Journal of Stem cells and Regenerative Medicine, 8(3), 181–189.Google Scholar
  84. 84.
    Moniche, F., Gonzalez, A., Gonzalez-Marcos, J. R., Carmona, M., Pinero, P., Espigado, I., et al. (2012). Intra-arterial bone marrow mononuclear cells in ischemic stroke: A pilot clinical trial. Stroke, 43(8), 2242–2244.Google Scholar
  85. 85.
    Savitz, S. I., Misra, V., Kasam, M., Juneja, H., Cox Jr., C. S., Alderman, S., Aisiku, I., Kar, S., Gee, A., & Grotta, J. C. (2011). Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Annals of Neurology, 70(1), 59–69.Google Scholar
  86. 86.
    Prasad, K., Sharma, A., Garg, A., Mohanty, S., Bhatnagar, S., Johri, S., Singh, K. K., Nair, V., Sarkar, R. S., Gorthi, S. P., Hassan, K. M., Prabhakar, S., Marwaha, N., Khandelwal, N., Misra, U. K., Kalita, J., Nityanand, S., & InveST Study Group. (2014). Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke, 45, 3618–3624.Google Scholar
  87. 87.
    Kumar, A., Prasad, M., Jali, V. P., Pandit, A. K., Misra, S., Kumar, P., Chakravarty, K., Kathuria, P., & Gulati, A. (2017). Bone marrow mononuclear cell therapy in ischaemic stroke: A systematic review. Acta Neurologica Scandinavica, 135(5), 496–506.Google Scholar
  88. 88.
    Detante, O., Muir, K., & Jolkkonen, J. (2018). Cell therapy in stroke-cautious Steps towards a clinical treatment. Translational Stroke Research, 9(4), 321–332.Google Scholar
  89. 89.
    Liu, X., Ye, R., Yan, T., Yu, S. P., Wei, L., Xu, G., Fan, X., Jiang, Y., Stetler, R. A., Liu, G., & Chen, J. (2014). Cell based therapies for ischemic stroke: From basic science to bedside. Progress in Neurobiology, 115, 92–115.Google Scholar
  90. 90.
    Marei, H. E., Hasan, A., Rizzi, R., Althani, A., Afifi, N., Cenciarelli, C., Caceci, T., & Shuaib, A. (2018). Potential of stem cell-based therapy for ischemic stroke. Frontiers in Neurology, 9, 34.Google Scholar
  91. 91.
    Wu, Q., Wang, Y., Demaerschalk, B. M., Ghimire, S., Wellik, K. E., & Qu, W. (2017). Bone marrow stromal cell therapy for ischemic stroke: A meta-analysis of randomized control animal trials. International Journal of Stroke, 12(3), 273–284.Google Scholar
  92. 92.
    Kern, S., Eichler, H., Stoeve, J., Kluter, H., & Bieback, K. (2006). Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells, 24(5), 1294–1301.Google Scholar
  93. 93.
    Ikegame, Y., Yamashita, K., Hayashi, S.-I., Mizuno, H., Tawada, M., You, F., Yamada, K., Tanaka, Y., Egashira, Y., Nakashima, S., Yoshimura, S. I., & Iwama, T. (2011). Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy, 13, 675–685.Google Scholar
  94. 94.
    Nakagami, H., Morishita, R., Maeda, K., Kikuchi, Y., Ogihara, T., & Kaneda, Y. (2006). Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. Journal of Atherosclerosis and Thrombosis, 13, 77–81.Google Scholar
  95. 95.
    Bieback, K., Kinzebach, S., & Karagianni, M. (2011). Translating research into clinical scale manufacturing of mesenchymal stromal cells. Stem Cells International, 2010, 193519.Google Scholar
  96. 96.
    Nimgaonkar, M. T., Roscoe, R. A., Persichetti, J., Rybka, W. B., Winkelstein, A., & Ball, E. D. (1995). A unique population of CD34+ cells in cord blood. Stem Cells, 13(2), 158–166.Google Scholar
  97. 97.
    Tatsumi, K., Ohashi, K., Matsubara, Y., Kohori, A., Ohno, T., Kakidachi, H., Horii, A., Kanegae, K., Utoh, R., Iwata, T., & Okano, T. (2013). Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochemical and Biophysical Research Communications, 431, 203–209.Google Scholar
  98. 98.
    Tepper, O. M., Galiano, R. D., Capla, J. M., Kalka, C., Gagne, P. J., Jacobowitz, G. R., Levine, J. P., & Gurtner, G. C. (2002). Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation, 106, 2781–2786.Google Scholar
  99. 99.
    Caballero, S., Sengupta, N., Afzal, A., Chang, K. H., Li Calzi, S., Guberski, D. L., Kern, T. S., & Grant, M. B. (2007). Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes, 56(4), 960–967.Google Scholar
  100. 100.
    Chen, J., Ye, X., Yan, T., Zhang, C., Yang, X.-P., Cui, X., Cui, Y., Zacharek, A., Roberts, C., Liu, X., Dai, X., Lu, M., & Chopp, M. (2011). Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke, 42, 3551–3558.Google Scholar
  101. 101.
    Ding, G., Chen, J., Chopp, M., Li, L., Yan, T., Li, Q., Cui, C., Davarani, S. P. N., & Jiang, Q. (2016). Cell treatment for stroke in type two diabetic rats improves vascular permeability measured by MRI. PLoS One, 11, e0149147.Google Scholar
  102. 102.
    Minnerup, J., Wagner, D. C., Strecker, J. K., Posel, C., Sevimli-Abdis, S., Schmidt, A., et al. (2014). Bone marrow-derived mononuclear cells do not exert acute neuroprotection after stroke in spontaneously hypertensive rats. Frontiers in Cellular Neuroscience, 7, 288.Google Scholar
  103. 103.
    Caplan, A. I. (2009). Why are MSCs therapeutic? New data: New insight. The Journal of Pathology, 217(2), 318–324.Google Scholar
  104. 104.
    Zaim, M., Karaman, S., Cetin, G., & Isik, S. (2012). Donor age and long-term culture affect differentiation and proliferation of human bone marrow mesenchymal stem cells. Annals of Hematology, 91(8), 1175–1186.Google Scholar
  105. 105.
    Shen, L. H., Li, Y., Chen, J., Cui, Y., Zhang, C., Kapke, A., et al. (2007). One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke. Stroke, 38, 2150–2156.Google Scholar
  106. 106.
    Zacharek, A., Shehadah, A., Chen, J., Cui, X., Roberts, C., Lu, M., & Chopp, M. (2010). Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke, 41, 524–530.Google Scholar
  107. 107.
    Lees, J. S., Sena, E. S., Egan, K. J., Antonic, A., Koblar, S. A., Howells, D. W., & Macleod, M. R. (2012). Stem cell-based therapy for experimental stroke: A systematic review and meta-analysis. International Journal of Stroke, 7(7), 582–588.Google Scholar
  108. 108.
    Altmann, P., Mildner, M., Haider, T., Traxler, D., Beer, L., Ristl, R., et al. (2014). Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia. F1000Res, 3, 131.Google Scholar
  109. 109.
    Kim, S. J., Moon, G. J., & Bang, O. Y. (2013). Biomarkers for stroke. Journal of Stroke, 15(1), 27–37.Google Scholar
  110. 110.
    Gyorgy, B., Szabo, T. G., Pasztoi, M., Pal, Z., Misjak, P., Aradi, B., et al. (2011). Membrane vesicles, current state-of-the-art: Emerging role of extracellular vesicles. Cellular and Molecular Life Sciences, 68(16), 2667–2688.Google Scholar
  111. 111.
    Venkat, P., Chopp, M., & Chen, J. (2018). Cell-based and exosome therapy in diabetic stroke. Stem Cells Translational Medicine, 7(6), 451–455.Google Scholar
  112. 112.
    Doeppner, T. R., Herz, J., Görgens, A., Schlechter, J., Ludwig, A.-K., Radtke, S., de Miroschedji, K., Horn, P. A., Giebel, B., & Hermann, D. M. (2015). Extracellular vesicles improve post-stroke Neuroregeneration and prevent Postischemic immunosuppression. Stem Cells Translational Medicine, 4, 1131–1143.Google Scholar
  113. 113.
    Modo, M., Ambrosio, F., Friedlander, R. M., Badylak, S. F., & Wechsler, L. R. (2013). Bioengineering solutions for neural repair and recovery in stroke. Current Opinion in Neurology, 26(6), 626–631.Google Scholar
  114. 114.
    Yu, F., & Morshead, C. M. (2011). Adult stem cells and bioengineering strategies for the treatment of cerebral ischemic stroke. Current Stem Cell Research & Therapy, 6(3), 190–207.Google Scholar
  115. 115.
    Moshayedi, P., Nih, L. R., Llorente, I. L., Berg, A. R., Cinkornpumin, J., Lowry, W. E., Segura, T., & Carmichael, S. T. (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.Google Scholar
  116. 116.
    Linnik, M. D., Zahos, P., Geschwind, M. D., & Federoff, H. J. (1995). Expression of bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia. Stroke, 26, 1670–1674 discussion 1675.Google Scholar
  117. 117.
    Hermann, D. M., Kilic, E., Kügler, S., Isenmann, S., & Bähr, M. (2001). Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiology of Disease, 8, 655–666.Google Scholar
  118. 118.
    Badin, R. A., Lythgoe, M. F., van der Weerd, L., Thomas, D. L., Gadian, D. G., & Latchman, D. S. (2006). Neuroprotective effects of virally delivered HSPs in experimental stroke. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 26, 371–381.Google Scholar
  119. 119.
    Hoehn, B., Yenari, M. A., Sapolsky, R. M., & Steinberg, G. K. (2003). Glutathione peroxidase overexpression inhibits cytochrome C release and proapoptotic mediators to protect neurons from experimental stroke. Stroke, 34, 2489–2494.Google Scholar
  120. 120.
    Sugiura, S., Kitagawa, K., Tanaka, S., Todo, K., Omura-Matsuoka, E., Sasaki, T., Mabuchi, T., Matsushita, K., Yagita, Y., & Hori, M. (2005). Adenovirus-mediated gene transfer of heparin-binding epidermal growth factor-like growth factor enhances neurogenesis and angiogenesis after focal cerebral ischemia in rats. Stroke, 36, 859–864.Google Scholar
  121. 121.
    Kondziolka, D., Steinberg, G. K., Wechsler, L., Meltzer, C. C., Elder, E., Gebel, J., DeCesare, S., Jovin, T., Zafonte, R., Lebowitz, J., Flickinger, J. C., Tong, D., Marks, M. P., Jamieson, C., Luu, D., Bell-Stephens, T., & Teraoka, J. (2005). Neurotransplantation for patients with subcortical motor stroke: A phase 2 randomized trial. Journal of Neurosurgery, 103(1), 38–45.Google Scholar
  122. 122.
    Jin, K., Sun, Y., Xie, L., Mao, X. O., Childs, J., Peel, A., Logvinova, A., Banwait, S., & Greenberg, D. A. (2005). Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiology of Disease, 18, 366–374.Google Scholar
  123. 123.
    Zhang, L., Li, Y., Romanko, M., Kramer, B. C., Gosiewska, A., Chopp, M., & Hong, K. (2012). Different routes of administration of human umbilical tissue-derived cells improve functional recovery in the rat after focal cerebral ischemia. Brain Research, 1489, 104–112.Google Scholar
  124. 124.
    Schaller, B., Merlo, A., Kirsch, E., Lehmann, K., Huber, P. R., Lyrer, P., Steck, A. J., & Gratzl, O. (1998). Prostate-specific antigen in the cerebrospinal fluid leads to diagnosis of solitary cauda equina metastasis: A unique case report and review of the literature. British Journal of Cancer, 77(12), 2386–2389.Google Scholar
  125. 125.
    Doeppner, T. R., Kaltwasser, B., Teli, M. K., Sanchez-Mendoza, E. H., Kilic, E., Bähr, M., & Hermann, D. M. (2015). Post-stroke transplantation of adult subventricular zone derived neural progenitor cells — A comprehensive analysis of cell delivery routes and their underlying mechanisms. Experimental Neurology, 273, 45–56.Google Scholar
  126. 126.
    Kasahara, Y., Yamahara, K., Soma, T., Stern, D. M., Nakagomi, T., Matsuyama, T., & Taguchi, A. (2016). Transplantation of hematopoietic stem cells: Intra-arterial versus intravenous administration impacts stroke outcomes in a murine model. Translational Research, 176, 69–80.Google Scholar
  127. 127.
    Pendharkar, A. V., Chua, J. Y., Andres, R. H., Wang, N., Gaeta, X., Wang, H., de, A., Choi, R., Chen, S., Rutt, B. K., Gambhir, S. S., & Guzman, R. (2010). Biodistribution of neural stem cells after intravascular therapy for hypoxic–ischemia. Stroke, 41, 2064–2070.Google Scholar
  128. 128.
    Borlongan, C. V., Hadman, M., Sanberg, C. D., & Sanberg, P. R. (2004). Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke, 35, 2385–2389.Google Scholar
  129. 129.
    Danielyan, L., Schäfer, R., von Ameln-Mayerhofer, A., Buadze, M., Geisler, J., Klopfer, T., Burkhardt, U., Proksch, B., Verleysdonk, S., Ayturan, M., Buniatian, G. H., Gleiter, C. H., & Frey II, W. H. (2009). Intranasal delivery of cells to the brain. European Journal of Cell Biology, 88, 315–324.Google Scholar
  130. 130.
    Ohshima, M., Taguchi, A., Tsuda, H., Sato, Y., Yamahara, K., Harada-Shiba, M., Miyazato, M., Ikeda, T., Iida, H., & Tsuji, M. (2015). Intraperitoneal and intravenous deliveries are not comparable in terms of drug efficacy and cell distribution in neonatal mice with hypoxia-ischemia. Brain & Development, 37, 376–386.Google Scholar
  131. 131.
    Duan, X., Lu, L., Wang, Y., Zhang, F., Mao, J., Cao, M., Lin, B., Zhang, X., Shuai, X., & Shen, J. (2017). The long-term fate of mesenchymal stem cells labeled with magnetic resonance imaging-visible polymersomes in cerebral ischemia. International Journal of Nanomedicine, 12, 6705–6719.Google Scholar
  132. 132.
    Chen, C., Lin, X., Wang, J., Tang, G., Mu, Z., Chen, X., Xu, J., Wang, Y., Zhang, Z., & Yang, G. Y. (2014). Effect of HMGB1 on the paracrine action of EPC promotes post-ischemic neovascularization in mice. Stem Cells, 32(10), 2679–2689.Google Scholar
  133. 133.
    Satani, N., & Savitz, S. I. (2016). Is immunomodulation a principal mechanism underlying how cell-based therapies enhance stroke recovery? Neurotherapeutics, 13, 775–782.Google Scholar
  134. 134.
    Fischer, U. M., Harting, M. T., Jimenez, F., Monzon-Posadas, W. O., Xue, H., Savitz, S. I., et al. (2008). Pulmonary passage is a major obstacle for intravenous stem cell delivery: The pulmonary first-pass effect. Stem Cells and Development, 18, 683–692.Google Scholar
  135. 135.
    Vendrame, M., Gemma, C., Pennypacker, K. R., Bickford, P. C., Davis Sanberg, C., Sanberg, P. R., & Willing, A. E. (2006). Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Experimental Neurology, 199, 191–200.Google Scholar
  136. 136.
    Nystedt, J., Anderson, H., Tikkanen, J., Pietilä, M., Hirvonen, T., Takalo, R., Heiskanen, A., Satomaa, T., Natunen, S., Lehtonen, S., Hakkarainen, T., Korhonen, M., Laitinen, S., Valmu, L., & Lehenkari, P. (2013). Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells. Stem Cells, 31, 317–326.Google Scholar
  137. 137.
    Offner, H., Subramanian, S., Parker, S. M., Wang, C., Afentoulis, M. E., Lewis, A., Vandenbark, A. A., & Hurn, P. D. (2006). Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. The Journal of Immunology, 176, 6523–6531.Google Scholar
  138. 138.
    Chen, J., Li, Y., Wang, L., Lu, M., Zhang, X., & Chopp, M. (2001). Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. Journal of the Neurological Sciences, 189(1–2), 49–57.Google Scholar
  139. 139.
    Li, Y., Chen, J., Zhang, C. L., Wang, L., Lu, D., Katakowski, M., Gao, Q., Shen, L. H., Zhang, J., Lu, M., & Chopp, M. (2005). Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia, 49, 407–417.Google Scholar
  140. 140.
    Shen, L. H., Li, Y., Chen, J., Zacharek, A., Gao, Q., Kapke, A., Lu, M., Raginski, K., Vanguri, P., Smith, A., & Chopp, M. (2007). Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. Journal of Cerebral Blood Flow & Metabolism, 27, 6–13.Google Scholar
  141. 141.
    Yang, B., Strong, R., Sharma, S., Brenneman, M., Mallikarjunarao, K., Xi, X., Grotta, J. C., Aronowski, J., & Savitz, S. I. (2011). Therapeutic time window and dose response of autologous bone marrow mononuclear cells for ischemic stroke. Journal of Neuroscience Research, 89, 833–839.Google Scholar
  142. 142.
    Poittevin, M., Deroide, N., Azibani, F., Delcayre, C., Giannesini, C., Levy, B. I., Pocard, M., & Kubis, N. (2013). Glatiramer acetate administration does not reduce damage after cerebral ischemia in mice. Journal of Neuroimmunology, 254, 55–62.Google Scholar
  143. 143.
    Acosta, S. A., Tajiri, N., Hoover, J., Kaneko, Y., & Borlongan, C. V. (2015). Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke, 46, 2616–2627.Google Scholar
  144. 144.
    Boltze, J., Schmidt, U. R., Reich, D. M., Kranz, A., Reymann, K. G., Strassburger, M., Lobsien, D., Wagner, D. C., Förschler, A., & Schäbitz, W. R. (2012). Determination of the therapeutic time window for human umbilical cord blood mononuclear cell transplantation following experimental stroke in rats. Cell Transplantation, 21, 1199–1211.Google Scholar
  145. 145.
    Lipsanen, A., & Jolkkonen, J. (2011). Experimental approaches to study functional recovery following cerebral ischemia. Cellular and Molecular Life Sciences, 68(18), 3007–3017.Google Scholar
  146. 146.
    Langhorne, P., Bernhardt, J., & Kwakkel, G. (2011). Stroke rehabilitation. Lancet, 377(9778), 1693–1702.Google Scholar
  147. 147.
    Boltze, J., Lukomska, B., Jolkkonen, J., & consortium MI. (2014). Mesenchymal stromal cells in stroke: Improvement of motor recovery or functional compensation? Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 34, 1420–1421.Google Scholar
  148. 148.
    Kase, C. S., Wolf, P. A., Kelly-Hayes, M., Kannel, W. B., Beiser, A., & D’Agostino, R. B. (1998). Intellectual decline after stroke: The Framingham study. Stroke, 29, 805–812.Google Scholar
  149. 149.
    Claesson, L., Lindén, T., Skoog, I., & Blomstrand, C. (2005). Cognitive impairment after stroke – Impact on activities of daily living and costs of Care for Elderly People. Cerebrovascular Diseases, 19, 102–109.Google Scholar
  150. 150.
    Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N. A., Müller, F.-J., Loring, J. F., et al. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proceedings of the National Academy of Sciences, 106, 13594–13599.Google Scholar
  151. 151.
    Chen, L., Zhang, G., Khan, A. A., Guo, X., & Gu, Y. (2016). Clinical efficacy and meta-analysis of stem cell therapies for patients with brain ischemia. Stem Cells International, 2016, 6129579.Google Scholar
  152. 152.
    Díez-Tejedor, E., Gutiérrez-Fernández, M., Martínez-Sánchez, P., Rodríguez-Frutos, B., Ruiz-Ares, G., Lara, M. L., & Gimeno, B. F. (2014). 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. Journal of Stroke and Cerebrovascular Diseases: The Official Journal of National Stroke Association, 23, 2694–2700.Google Scholar
  153. 153.
    Bhatia, V., Gupta, V., Khurana, D., Sharma, R. R., & Khandelwal, N. (2018). Randomized assessment of the safety and efficacy of intra-arterial infusion of autologous stem cells in subacute ischemic stroke. AJNR. American Journal of Neuroradiology, 39(5), 899–904.Google Scholar
  154. 154.
    Steinberg, G. K., Kondziolka, D., Wechsler, L. R., Lunsford, L. D., Coburn, M. L., Billigen, J. B., Kim, A. S., Johnson, J. N., Bates, D., King, B., Case, C., McGrogan, M., Yankee, E. W., & Schwartz, N. E. (2016). Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: A phase 1/2a study. Stroke, 47, 1817–1824.Google Scholar
  155. 155.
    Banerjee, S., Bentley, P., Hamady, M., Marley, S., Davis, J., Shlebak, A., Nicholls, J., Williamson, D. A., Jensen, S. L., Gordon, M., Habib, N., & Chataway, J. (2014). Intra-arterial Immunoselected CD34+ stem cells for acute ischemic stroke. Stem Cells Translational Medicine, 3(11), 1322–1330.Google Scholar
  156. 156.
    Laskowitz, D. T., Bennett, E. R., Durham, R. J., Volpi, J. J., Wiese, J. R., Frankel, M., Shpall, E., Wilson, J. M., Troy, J., & Kurtzberg, J. (2018). Allogeneic umbilical cord blood infusion for adults with ischemic stroke: Clinical outcomes from a phase 1 safety study. Stem Cells Translational Medicine, 7, 521–529.Google Scholar
  157. 157.
    Moniche, F., Escudero, I., Zapata-Arriaza, E., Usero-Ruiz, M., Prieto-Leon, M., de la Torre, J., et al. (2015). Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): Protocol of a phase II, randomized, dose-finding, controlled multicenter trial. International Journal of Stroke, 10(7), 1149–1152.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.INSERM U965ParisFrance
  2. 2.Sorbonne Paris CitéUniversité Paris DiderotParisFrance
  3. 3.Service de Physiologie Clinique-Explorations Fonctionnelles, AP-HPHôpital LariboisièreParisFrance

Personalised recommendations