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

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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.

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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

References

  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. 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. 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.

    Article  PubMed  Google Scholar 

  4. Mathers, C. D., & Loncar, D. (2006). Projections of global mortality and burden of disease from 2002 to 2030. PLoS Medicine, 3, e442.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  9. Ekdahl, C. T., Kokaia, Z., & Lindvall, O. (2009). Brain inflammation and adult neurogenesis: The dual role of microglia. Neuroscience, 158, 1021–1029.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  12. Cramer, S. C., & Chopp, M. (2000). Recovery recapitulates ontogeny. Trends in Neurosciences, 23, 265–271.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. Mergenthaler, P., & Meisel, A. (2012). Do stroke models model stroke? Disease Models & Mechanisms, 5, 718–725.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  52. Esquiva, G., Grayston, A., & Revascularization, R. A. (2018). Endothelial progenitor cells in stroke. American Journal of Physiology. Cell Physiology, 315, C664–C674.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  55. Rodgerson, D. O., & Harris, A. G. (2011). A comparison of stem cells for therapeutic use. Stem Cell Reviews, 7(4), 782–796.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  61. Kassem, M. (2004). Mesenchymal stem cells: Biological characteristics and potential clinical applications. Cloning and Stem Cells, 6, 369–374.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  63. Dharmasaroja, P. (2009). Bone marrow-derived mesenchymal stem cells for the treatment of ischemic stroke. Journal of Clinical Neuroscience, 16(1), 12–20.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  65. Kalladka, D., & Muir, K. W. (2014). Brain repair: Cell therapy in stroke. Stem Cells and Cloning : Advances and Applications, 7, 31–44.

    CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  71. trials RaMaEc. RESSTORE REgenerative Stem cell therapy for STroke in Europe. https://clinicaltrials.gov/ct2/show/NCT03570450. Accessed 27 June 2018.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Uccelli, A., Moretta, L., & Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nature Reviews. Immunology, 8(9), 726–736.

    Article  CAS  PubMed  Google Scholar 

  76. Ankrum, J. A., Ong, J. F., & Karp, J. M. (2014). Mesenchymal stem cells: immune evasive, not immune privileged. Nature Biotechnology, 32, 252–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  95. Bieback, K., Kinzebach, S., & Karagianni, M. (2011). Translating research into clinical scale manufacturing of mesenchymal stromal cells. Stem Cells International, 2010, 193519.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Caplan, A. I. (2009). Why are MSCs therapeutic? New data: New insight. The Journal of Pathology, 217(2), 318–324.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kim, S. J., Moon, G. J., & Bang, O. Y. (2013). Biomarkers for stroke. Journal of Stroke, 15(1), 27–37.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Venkat, P., Chopp, M., & Chen, J. (2018). Cell-based and exosome therapy in diabetic stroke. Stem Cells Translational Medicine, 7(6), 451–455.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  133. Satani, N., & Savitz, S. I. (2016). Is immunomodulation a principal mechanism underlying how cell-based therapies enhance stroke recovery? Neurotherapeutics, 13, 775–782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  145. Lipsanen, A., & Jolkkonen, J. (2011). Experimental approaches to study functional recovery following cerebral ischemia. Cellular and Molecular Life Sciences, 68(18), 3007–3017.

    Article  CAS  PubMed  Google Scholar 

  146. Langhorne, P., Bernhardt, J., & Kwakkel, G. (2011). Stroke rehabilitation. Lancet, 377(9778), 1693–1702.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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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.

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  1. INSERM U965, F-75475, Paris, France

    Gabrielle Mangin & Nathalie Kubis

  2. Sorbonne Paris Cité, Université Paris Diderot, F-75475, Paris, France

    Nathalie Kubis

  3. Service de Physiologie Clinique-Explorations Fonctionnelles, AP-HP, Hôpital Lariboisière, 2 rue Ambroise Paré, F-75475, Paris, France

    Nathalie Kubis

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Mangin, G., Kubis, N. Cell Therapy for Ischemic Stroke: How to Turn a Promising Preclinical Research into a Successful Clinical Story. Stem Cell Rev and Rep 15, 176–193 (2019). https://doi.org/10.1007/s12015-018-9864-3

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