Autologous Endothelial Progenitor Cells Transplantation for Acute Ischemic Stroke: A 4-Year Follow-Up Study

Jie Fang, Yang Guo, Sheng Tan, Zhanhui Li, Huifang Xie, Pingyan Chen, Kai Wang, Zhicong He, Peng He, Yiquan Ke, Xiaodan Jiang, Zhenzhou Chen, Jie Fang, Yang Guo, Sheng Tan, Zhanhui Li, Huifang Xie, Pingyan Chen, Kai Wang, Zhicong He, Peng He, Yiquan Ke, Xiaodan Jiang, Zhenzhou Chen

Abstract

Transplantation of endothelial progenitor cells (EPCs) is a proven safe and effective method for treatment of cerebral ischemia in animal experiments. However, safety and efficacy need to be determined in clinical trials. We performed a two-center, randomized, placebo-controlled phase I/IIa trial with blinded outcome assessment on 18 patients with acute cerebral infarct within the middle cerebral artery territory, and followed for up to 4 years. Autologous ex vivo expanded EPCs were injected intravenously in the EPC group, and patients who received saline or autologous bone marrow stromal cells served as control groups. Mortality of any cause, adverse events, and new-onset comorbidities were monitored. Changes in neurological deficits were assessed at different time points. We found no toxicity events or infusional or allergic reactions in any treated group. Three patients in the placebo group died during the 4-year follow-up. We found that the EPC group had fewer serious adverse events compared with the placebo-controlled group, although there were no statistical differences in mortality among the three groups. Furthermore, there was no significant difference in neurological or functional improvement observed among the three groups, except for the Scandinavia Stroke Scale score at 3 months between the EPC group and placebo-controlled group. Autologous transplantation of EPCs appears to improve long-term safety in acute cerebral infarct patients, supporting the feasibility of this novel method for treatment of ischemic stroke (ClinicalTrials.gov: NCT01468064). Stem Cells Translational Medicine 2019;8:14-21.

Keywords: Bone marrow stromal cells; Clinical trial; Endothelial progenitor cells; Stroke; Transplantation.

© 2018 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
Study profile. Abbreviations: BMSCs, bone marrow stromal cells; EPCs, endothelial progenitor cells; MCA, middle cerebral artery.
Figure 2
Figure 2
Change of neurological or functional outcome from baseline to 48 months. Gradual improvement of neurological function measured by NIHSS (A), SSS (B), BI (C), and mRS (D) could be observed in the EPCs group. However, no significant difference of the scores at each time point could be observed between arms, except for the SSS score at 3‐month time point between the EPCs group and the placebo‐controlled group. *p < .05. Abbreviations: BMSCs, bone marrow stromal cells; EPCs, endothelial progenitor cells; SSS, Scandinavia Stroke Scale .

References

    1. Benjamin EJ, Blaha MJ, Chiuve SE et al. Heart Disease and Stroke Statistics‐2017 Update: A Report From the American Heart Association. Circulation 2017;135(10):e146–e603.
    1. Society of neurology, Chinese Medical Association. Guidelines for Acute Ischaemic Stroke Diagnosis and Therapy. Chi J Neuro 2015;48:246–257.
    1. Nguyen TN, Babikian VL, Romero R et al. Intra‐arterial treatment methods in acute stroke therapy. Front Neurol 2011;2:9.
    1. Azad TD, Veeravagu A, Steinberg GK. Neurorestoration after stroke. Neurosurg Focus 2016;40(5):E2.
    1. Wan H, Li F, Zhu L et al. Update on therapeutic mechanism for bone marrow stromal cells in ischemic stroke. J Mol Neurosci 2014;52(2):177–185.
    1. Maria Ferri AL, Bersano A, Lisini D et al. Mesenchymal stem cells for ischemic stroke: Progress and possibilities. Curr Med Chem 2016;23(16):1598–1608.
    1. Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967.
    1. Galimi F, Summers RG, van Praag H et al. A role for bone marrow‐derived cells in the vasculature of noninjured CNS. Blood 2005;105:2400–2412.
    1. Zhang ZG, Zhang L, Jiang Q et al. Bone marrow‐derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 2002;90:284–288.
    1. Hill JM, Zalos G, Halcox JP et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593–600.
    1. Ohta T, Kikuta K, Imamura H et al. Administration of ex vivo‐expanded bone marrow‐derived endothelial progenitor cells attenuates focal cerebral ischemia‐reperfusion injury in rats. Neurosurgery 2006;59:679–686.
    1. Chen ZZ, Jiang XD, Zhang LL et al. Beneficial effect of autologous transplantation of bone marrow stromal cells and endothelial progenitor cells on cerebral ischemia in rabbits. Neurosci. Lett. 2008;445:36–41.
    1. Geng J, Wang L, Qu M et al. Endothelial progenitor cells transplantation attenuated blood‐brain barrier damage after ischemia in diabetic mice via HIF‐1alpha. Stem Cell Res Ther 2017;8:163.
    1. Bai YY, Peng XG, Wang LS et al. Bone marrow endothelial progenitor cell transplantation after ischemic stroke: An investigation into its possible mechanism. CNS Neurosci Ther 2015;21:877–886.
    1. Li YF, Ren LN, Guo G et al. Endothelial progenitor cells in ischemic stroke: An exploration from hypothesis to therapy. J Hematol Oncol 2015;8:33.
    1. Bang OY, Lee JS, Lee PH et al. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005;57:874–882.
    1. Lee JS, Hong JM, Moon GJ et al. A long‐term follow‐up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 2010;28:1099–1106.
    1. Steinberg GK, Kondziolka D, Wechsler LR et al. Clinical outcomes of transplanted modified bone marrow‐derived mesenchymal stem cells in stroke: A phase 1/2a study. Stroke 2016;47:1817–1824.
    1. Singla A, Hogan WJ, Ansell SM et al. Incidence of supraventricular arrhythmias during autologous peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2013;19:1233–1237.
    1. Tonorezos ES, Stillwell EE, Calloway JJ et al. Arrhythmias in the setting of hematopoietic cell transplants. Bone Marrow Transplant 2015;50:1212–1216.
    1. Tang H, Xiang Y, Jiang X et al. Dual expression of hTERT and VEGF prolongs life span and enhances angiogenic ability of aged BMSCs. Biochem Biophys Res Commun 2013;440:502–508.
    1. Hess DC, Sila CA, Furlan AJ et al. A double‐blind placebo‐controlled clinical evaluation of MultiStem for the treatment of ischemic stroke. Int J Stroke 2014;9:381–286.
    1. Hess DC, Wechsler LR, Clark WM et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double‐blind, placebo‐controlled, phase 2 trial. Lancet Neurol 2017;16:360–368.
    1. Moniche F, Gonzalez A, Gonzalez‐Marcos JR et al. Intra‐arterial bone marrow mononuclear cells in ischemic stroke: A pilot clinical trial. Stroke 2012;43:2242–2254.
    1. Friedrich MA, Martins MP, Araujo MD et al. 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–S21.
    1. Prasad K, Sharma A, Garg A et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke 2014;45:3618–3624.
    1. Taljaard M, Ward MR, Kutryk MJ et al. Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT‐AMI): The first randomized placebo‐controlled trial of enhanced progenitor cell therapy for acute myocardial infarction. Am Heart J 2010;159:354–360.
    1. Zhu J, Song J, Yu L et al. Safety and efficacy of autologous thymosin beta4 pre‐treated endothelial progenitor cell transplantation in patients with acute ST segment elevation myocardial infarction: A pilot study. Cytotherapy 2016;18:1037–1042.
    1. D'Avola D, Fernandez‐Ruiz V, Carmona‐Torre F et al. Phase 1‐2 pilot clinical trial in patients with decompensated liver cirrhosis treated with bone marrow‐derived endothelial progenitor cells. Transl Res 2017;188:80–91 e2.
    1. Lara‐Hernandez R, Lozano‐Vilardell P, Blanes P et al. Safety and efficacy of therapeutic angiogenesis as a novel treatment in patients with critical limb ischemia. Ann Vasc Surg 2010;24:287–294.
    1. Lasala GP, Silva JA, Gardner PA et al. Combination stem cell therapy for the treatment of severe limb ischemia: Safety and efficacy analysis. Angiology 2010;61:551–556.
    1. Zhu JH, Wang XX, Zhang FR et al. Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open‐label pilot study. Pediatr Transplant 2008;12:650–655.
    1. Wang XX, Zhang FR, Shang YP et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007;49:1566–1571.
    1. Kalladka D, Sinden J, Pollock K et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): A phase 1, first‐in‐man study. Lancet 2016;388:787–796.
    1. Cohen PD, Isaacs T, Willocks P et al. Sham neurosurgical procedures: The patients' perspective. Lancet Neurol 2012;11:1022.

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