Clinical Studies of Bone Marrow-Derived Stem Cell Therapy in Stroke Patients

  • Francisco MonicheEmail author
  • Irene Escudero
  • Elena Zapata
  • Fernando Mancha
  • Ángela Vega-Salvatierra
  • Blanca Pardo
  • Joan Montaner


Stroke is the leading cause of long-term disability in adults and the third cause of mortality worldwide. In the very acute phase of stroke, thrombolytics and endovascular thrombectomy can reduce stroke disability; however, only a small minority of patients receive these treatments. Once the neurological deficits are established, there are few options for recovery. In recent years, extensive cell therapy preclinical research has demonstrated a neurorestorative effect after cerebral ischemia. In cerebral ischemia animal models, bone marrow-derived stem cells improve neurological outcomes even in the long term, increasing brain plasticity and enhancing recovery mainly due to secretion of growth factors and cytokines.

In the bone marrow, different types of cells have been used for cell therapy in stroke. The first type of cells used for stroke and the most extensive studied in preclinical research are mesenchymal stem cells (MSCs). In recent years some other cells have been studied for stroke therapy with promising results, such as bone marrow mononuclear cells (BM-MNCs), hematopoietic stem cells (HSCs), and multipotent adult progenitor cells (MAPCs). Several phase I and II clinical trials have been published to date with these stem cells, which have already demonstrated the feasibility and safety of this therapy in the stroke setting. An increasing number of clinical trials, mainly with bone marrow MSCs and BM-MNCs, are ongoing to further assess the best dose, route, and timing of this therapy and to elucidate the efficacy cell therapy in stroke.


Patients Bone marrow-derived stem cells Therapy Stroke 



No disclosure information. This study is funded by grants from Junta de Andalucía [TCRM 0001/2006], Fundación Mutua Madrileña, and Instituto de Salud Carlos III [PI15/01197].


  1. 1.
    WHO MONICA Project Investigators. The World Health Organization MONICA Project (Monitoring trends and determinants in cardiovascular disease). J Clin Epidemiol. 1988;41:105–14.CrossRefGoogle Scholar
  2. 2.
    World Health Organization. The Atlas of disease cardiovascular and stroke.
  3. 3.
    Sudlow CLM, Warlow CP, for the International stroke incidence collaboration. Comparable studies of the incidence of stroke and its pathological types. Results from a International collaboration. Stroke. 1997;28:491–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Ovbiagele B, Goldstein LB, Higashida RT, Howard VJ, Johnston SC, Khavjou OA, Lackland DT, Lichtman JH, Mohl S, Sacco RL, Saver JL, Trogdon JG, on behalf of the American Heart Association Advocacy Coordinating Committee and Stroke Council. Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke. 2013;44:2361–75.CrossRefPubMedGoogle Scholar
  5. 5.
    Gustavsson A, Svensson M, et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21:718–79.CrossRefPubMedGoogle Scholar
  6. 6.
    Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012;379:2364–72.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Goyal M, Menon BK, van Zwam WH, et al, for the HERMES collaborators. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; published online Feb 18.
  8. 8.
    Muir KW, White P. HERMES: messenger for stroke interventional treatment. Lancet. 2016 Feb 18. [Epub ahead of print].Google Scholar
  9. 9.
    Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354:588–600.CrossRefPubMedGoogle Scholar
  10. 10.
    Dávalos A, Alvarez-Sabín J, Castillo J, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380:349–57.CrossRefPubMedGoogle Scholar
  11. 11.
    Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 2012;11:369–80.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Brenneman M, Sharma S, Harting M, Strong R, Cox Jr CS, Aronowski J, Grotta JC, Savitz SI. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. J Cereb Blood Flow Metab. 2010;30:140–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Fujita Y, Ihara M, Ushiki T, Hirai H, Kizaka-Kondoh S, Hiraoka M, Ito H, Takahashi R. Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow. Stroke. 2010;41:2938–43.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8:491–500.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yoo SW, Chang DY, Lee HS, Kim GH, Park JS, Ryu BY, et al. Immune suppression following mesenchymal stem cell transplantation in the ischemic brain is mediated by TGF-β. Neurobiol Dis. 2013;58:249–57.CrossRefPubMedGoogle Scholar
  16. 16.
    Banerjee S, Williamson DA, Habib N, Chataway J. The potential benefit of stem cell therapy after stroke: an update. Vasc Health Risk Manag. 2012;8:569–80.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rosado-de-Castro PH, Pimentel-Coelho PM, da Fonseca LM, de Freitas GR, Mendez-Otero R. The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev. 2013;22:2095–111.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells: the International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gupta PK, Chullikana A, Parakh R, Desai S, Das A, Gottipamula S, Krishnamurthy S, Anthony N, Pherwani A, Majumdar AS. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013;11:143.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chou SH, Lin SZ, Kuo WW, Pai P, Lin JY, Lai CH, Kuo CH, Lin KH, Tsai FJ, Huang CY. Mesenchymal stem cell insights: prospects in cardiovascular therapy. Cell Transplant. 2014;23:513–29.CrossRefPubMedGoogle Scholar
  22. 22.
    De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med. 2012;12:574–91.CrossRefPubMedGoogle Scholar
  23. 23.
    Vu Q, Xie K, Eckert M, Zhao W, Cramer SC. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82:1277–86.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73:778–86.CrossRefPubMedGoogle Scholar
  25. 25.
    Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003;92:692–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57:874–82.CrossRefPubMedGoogle Scholar
  27. 27.
    Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH. OY Bang and STARTING collaborators. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28:1099–106.CrossRefPubMedGoogle Scholar
  28. 28.
    Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, Waxman SG, Kocsis JD. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134:1790–807.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bhasin A, Srivastava MV, Mohanty S, Bhatia R, Kumaran SS, Bose S. Stem cell therapy: a clinical trial of stroke. Clin Neurol Neurosurg. 2013;115:1003–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Lu SS, Liu S, Zu QQ, Xu XQ, Yu J, Wang JW, Zhang Y, Shi HB. In vivo MR imaging of intraarterially delivered magnetically labeled mesenchymal stem cells in a canine stroke model. PLoS One. 2013;8:e54963.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, Kim AS, Johnson JN, Bates D, King B, Case C, McGrogan M, Yankee EW, Schwartz NE. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke. 2016;47(7):1817–24.CrossRefPubMedGoogle Scholar
  32. 32.
    Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, Pittenger MF, van Zijl PC, Huang J, Bulte JW. Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke. 2008;39:1569–74.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schwarting S, Litwak S, Hao W, Bähr M, Weise J, Neumann H. Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke. 2008;39:2867–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Taguchi A, Soma T, Tanaka H, et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest. 2004;114:330–8.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shyu WC, Lin SZ, Chiang MF, Su CY, Li H. Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci. 2006;26:3444–53.CrossRefPubMedGoogle Scholar
  36. 36.
    Chen DC, Lin SZ, Fan JR, Lin CH, Lee W, Lin CC, Liu YJ, Tsai CH, Chen JC, Cho DY, Lee CC, Shyu WC. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant. 2014;23:1599.PubMedGoogle Scholar
  37. 37.
    England TJ, Abaei M, Auer DP, Lowe J, Jones DR, Sare G, Walker M, Bath PM. Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial. Stroke. 2012;43:405–11.CrossRefPubMedGoogle Scholar
  38. 38.
    Banerjee S, Bentley P, Hamady M, Marley S, Davis J, Shlebak A, Nicholls J, Williamson DA, Jensen SL, Gordon M, Habib N, Chataway J. Intra-arterial immunoselected CD34+ stem cells for acute ischemic stroke. Stem Cells Transl Med. 2014;3:1322–30.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Nakano-Doi A, Nakagomi T, Fujikawa M, Nakagomi N, Kubo S, Lu S, et al. Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction. Stem Cells. 2010;28:1292–302.PubMedGoogle Scholar
  40. 40.
    Sharma S, Yang B, Strong R, Xi X, Brenneman M, Grotta JC, et al. Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke. J Neurosci Res. 2010;88:2869–76.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Suárez-Monteagudo C, Hernández-Ramírez P, Alvarez-González L, García-Maeso I, de la Cuétara-Bernal K, Castillo-Díaz L, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009;27:151–61.PubMedGoogle Scholar
  42. 42.
    Li ZM, Zhang ZT, Guo CJ, Geng FY, Qiang F, Wang LX. Autologous bone marrow mononuclear cell implantation for intracerebral hemorrhage-a prospective clinical observation. Clin Neurol Neurosurg. 2013;115:72–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Battistella V, de Freitas GR, da Fonseca LM, Mercante D, Gutfilen B, Goldenberg RC, Dias JV, Kasai-Brunswick TH, Wajnberg E, Rosado-de-Castro PH, Alves-Leon SV, Mendez-Otero R, Andre C. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med. 2011;6:45–52.CrossRefPubMedGoogle Scholar
  44. 44.
    Friedrich MA, Martins MP, Araújo MD, Klamt C, Vedolin L, Garicochea B, Raupp EF, Sartori El Ammar J, Machado DC, Costa JC, Nogueira RG, Rosado-de-Castro PH, Mendez-Otero R, Freitas GR. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 2012;21 Suppl 1:S13–21.CrossRefPubMedGoogle Scholar
  45. 45.
    Rosado de Castro PH, Schmidt FR, Battistella V, Lopes de Souza SA, Gutfilen B, Goldenberg RC, Kasai-Brunswick TH, Vairo L, Silva RM, et al. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen Med. 2013;8:145–55.CrossRefPubMedGoogle Scholar
  46. 46.
    Savitz SI, Misra V, Kasam M, Juneja H, Cox Jr CS, Alderman S, Aisiku I, Kar S, Gee A, Grotta JC. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011;70:59–69.CrossRefPubMedGoogle Scholar
  47. 47.
    Moniche F, Gonzalez A, Gonzalez-Marcos JR, Carmona M, Piñero P, Espigado I, Garcia-Solis D, Cayuela A, Montaner J, Boada C, Rosell A, Jimenez MD, Mayol A, Gil-Peralta A. Intra-arterial bone marrow mononuclear cells in ischemic stroke. A pilot clinical trial. Stroke. 2012;43:2242–4.CrossRefPubMedGoogle Scholar
  48. 48.
    El Khoury R, Misra V, Sharma S, Cox CS, Walker P, Grotta JC, et al. The effect of transcatheter injections on cell viability and cytokine release of mononuclear cells. AJNR Am J Neuroradiol. 2010;31:1488–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Prasad K, Mohanty S, Bhatia R, Srivastava MV, Garg A, Srivastava A, Goyal V, Tripathi M, Kumar A, Bal C, Vij A, Mishra NK. Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischaemic stroke: a pilot study. Indian J Med Res. 2012;136:221–8.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S, Singh KK, Nair V, Sarkar RS, Gorthi SP, Hassan KM, Prabhakar S, Marwaha N, Khandelwal N, Misra UK, Kalita J, Nityanand S, InveST Study Group. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45:3618–24.CrossRefPubMedGoogle Scholar
  51. 51.
    Yang B, Parsha K, Schaar K, Xi X, Aronowski J, Savitz SI. Various cell populations within the mononuclear fraction of bone marrow contribute to the beneficial effects of autologous bone marrow cell therapy in a rodent stroke model. Transl Stroke Res. 2016 Mar 20. [Epub ahead of print].Google Scholar
  52. 52.
    Womble TA, Green S, Shahaduzzaman M, Grieco J, Sanberg PR, Pennypacker KR, Willing AE. Monocytes are essential for the neuroprotective effect of human cord blood cells following middle cerebral artery occlusion in rat. Mol Cell Neurosci. 2014;59:76–84.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mora-Lee S, Sirerol-Piquer MS, Gutiérrez-Pérez M, Gomez-Pinedo U, Roobrouck VD, López T, Casado-Nieto M, Abizanda G, Rabena MT, Verfaille C, Prósper F, García-Verdugo JM. Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice. PLoS One. 2012;7(8):e43683.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Komatsu K, Honmou O, Suzuki J, Houkin K, Hamada H, Kocsis JD. Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia. Brain Res. 2010;1334:84–92.CrossRefPubMedGoogle Scholar
  55. 55.
    Yang B, Strong R, Sharma S, Brenneman M, Mallikarjunarao K, Xi X, Grotta JC, Aronowski J, Savitz SI. Therapeutic time window and dose response of autologous bone marrow mononuclear cells for ischemic stroke. J Neurosci Res. 2011;89:833–9.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    de Vasconcelos Dos Santos A, da Costa RJ, Diaz Paredes B, Moraes L, Jasmin, Giraldi-Guimarães A, Mendez-Otero R. Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats. Brain Res. 2010;1306:149–58.CrossRefPubMedGoogle Scholar
  57. 57.
    Moniche F, Montaner J, Gonzalez-Marcos JR, Carmona M, Piñero P, Espigado I, Cayuela A, Escudero I, de la Torre-Laviana FJ, Boada C, Rosell A, Mayol A, Jimenez MD, Gil-Peralta A, Gonzalez A. Intra-arterial bone marrow mononuclear cell transplantation correlates with GM-CSF, PDGF-BB, and MMP-2 serum levels in stroke patients: results from a clinical trial. Cell Transplant. 2014;23 Suppl 1:S57–64.CrossRefPubMedGoogle Scholar
  58. 58.
    Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18:683–92.CrossRefPubMedGoogle Scholar
  59. 59.
    Sharma A, Sane H, Gokulchandran N, Khopkar D, Paranjape A, Sundaram J, Gandhi S, Badhe P. Autologous bone marrow mononuclear cells intrathecal transplantation in chronic stroke. Stroke Res Treat. 2014;2014:234095.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, Battistella V, Goldenberg RC, Kasai-Brunswick T, Chagas CL, Wajnberg E, Maiolino A, Salles Xavier S, Andre C, Mendez-Otero R, de Freitas GR. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010;221:122–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J, Xu Y, Gautam SC, Chopp M. Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology. 2002;22:275–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Taguchi A, Sakai C, Soma T, Kasahara Y, Stern DM, Kajimoto K, Ihara M, Daimon T, Yamahara K, Doi K, Kohara N, Nishimura H, Matsuyama T, Naritomi H, Sakai N, Nagatsuka K. Intravenous autologous bone marrow mononuclear cell transplantation for stroke: phase1/2a clinical trial in a homogeneous group of stroke patients. Stem Cells Dev. 2015;24:2207–18.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Jeong H, Yim HW, Cho YS, Kim YI, Jeong SN, Kim HB, Oh IH. Efficacy and safety of stem cell therapies for patients with stroke: a systematic review and single arm meta-analysis. Int J Stem Cells. 2014;7:63–9.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Moniche F, Rosado-de-Castro PH, Escudero I, Zapata E, de la Torre Laviana FJ, Mendez-Otero R, Carmona M, Piñero P, Bustamante A, Lebrato L, Cabezas JA, Gonzalez A, de Freitas GR, Montaner J. Increasing dose of autologous bone marrow mononuclear cells (BM-MNCs) transplantation is related with stroke outcome. Results from a pooled analysis of two clinical trials. Stem Cells Int. 2016;2016:8657173.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Moniche F, Escudero I, Zapata-Arriaza E, Usero-Ruiz M, Prieto-León M, de la Torre J, Gamero MA, Tamayo JA, Ochoa-Sepúlveda JJ, Maestre J, Carmona M, Piñero P, Calderón-Cabrera C, Jimenez MD, Gonzalez A, Montaner J. 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. Int J Stroke. 2015;10:1149–52.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Francisco Moniche
    • 1
    • 2
    Email author
  • Irene Escudero
    • 1
  • Elena Zapata
    • 1
  • Fernando Mancha
    • 2
  • Ángela Vega-Salvatierra
    • 2
  • Blanca Pardo
    • 1
  • Joan Montaner
    • 2
  1. 1.Stroke Unit, Neurology Department, Instituto de Biomedicina de Sevilla-IBiSHospital Universitario Virgen del RocíoSevilleSpain
  2. 2.Instituto de Biomedicina de Sevilla-IBiSHospital Universitario Virgen del RocíoSevilleSpain

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