Regenerative strategies in treatment of stroke have great potential. The goal of the current study was to investigate safety of intrathecal administration of autologous CD34 positive cells in treatment of patients with poststroke. A total of eight male patients with a history of stroke were enrolled. The patients were treated subcutaneously with 5？μg/kg body weight rhG-CSF for 5 consecutive days, and then leukapheresis was performed to concentrate cells for CD34 positive immunoselection. All patients underwent intrathecal administration of CD34 positive cells via lumbar puncture. The primary outcome was safety evaluation for 12-month followup. In addition, behavioral function was evaluated with NIH stroke scale and Barthel index 1, 6, and 12 months after the last treatment, respectively. There were no major adverse events, and abnormal changes of blood tests during the whole treatment process included intrathecal administration and 12-month followup. The main message from the current study was that administration of G-CSF-mobilized autologous CD34 positive cells in patients with poststroke was safe. Future studies with larger population and control group are needed to confirm the safety and investigate the efficacy. 1. Introduction Cerebrovascular disorder, mainly including ischemic and hemorrhagic stroke, is the third cause of death after cardiovascular disease and cancer [1] and the leading cause of long-term disability in adults in China [2]. Although stroke mortality has declined in the past decades, its prevalence and morbidity increased dramatically because of enhanced stroke survival [3]. About 40% of stroke survivors have certain degree of impairment and 15–30% are severely disabled [4]. Therefore, every effort to prevent and treat stroke is urgently warranted. Up to date, many targets within the cascade of neuronal death have been identified. However, neuroprotective strategies in treating poststroke with sequela are controversial [5]. Since neural progenitor and stem cells were discovered in the adult brain for the first time in 1992 [6], different experimental stroke models indicated that neural progenitor and stem cells with activities of migration and differentiation are activated by hypoxia in brain [7, 8]. Increasing evidence from basic studies indicates that cord blood mononuclear cells, bone marrow mononuclear cells, and bone marrow stromal cells can survive in postischemia tissue and reduce neuronal damage when transplanted into rodents subjected to cerebral infarction [9–12]. Bone marrow-derived CD34 positive cells have previously
References
[1]
J. He, D. Gu, X. Wu et al., “Major causes of death among men and women in China,” The New England Journal of Medicine, vol. 353, no. 11, pp. 1124–1134, 2005.
[2]
R. Bonita, S. Mendis, T. Truelsen, J. Bogousslavsky, J. Toole, and F. Yatsu, “The global stroke initiative,” Lancet Neurology, vol. 3, no. 7, pp. 391–393, 2004.
[3]
B. Jiang, W.-Z. Wang, H. L. Chen et al., “Incidence and trends of stroke and its subtypes in China: results from three large cities,” Stroke, vol. 37, no. 1, pp. 63–68, 2006.
[4]
B. Bates, J. Y. Choi, P. W. Duncan et al., “Veterans Affairs/Department of Defense Clinical Practice Guideline for the Management of Adult Stroke Rehabilitation Care: executive summary,” Stroke, vol. 36, no. 9, pp. 2049–2056, 2005.
[5]
M. Fisher, G. Feuerstein, D. W. Howells et al., “Update of the stroke therapy academic industry roundtable preclinical recommendations,” Stroke, vol. 40, no. 6, pp. 2244–2250, 2009.
[6]
B. A. Reynolds and S. Weiss, “Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system,” Science, vol. 255, no. 5052, pp. 1707–1710, 1992.
[7]
T. Masuda, Y. Isobe, N. Aihara et al., “Increase in neurogenesis and neuroblast migration after a small intracerebral hemorrhage in rats,” Neuroscience Letters, vol. 425, no. 2, pp. 114–119, 2007.
[8]
R. Zhang, Z. Zhang, C. Zhang et al., “Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat,” Journal of Neuroscience, vol. 24, no. 25, pp. 5810–5815, 2004.
[9]
M. Brenneman, S. Sharma, M. Harting et al., “Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 1, pp. 140–149, 2010.
[10]
M. Hokari, S. Kuroda, H. Shichinohe, S. Yano, K. Hida, and Y. Iwasaki, “Bone marrow stromal cells protect and repair damaged neurons through multiple mechanisms,” Journal of Neuroscience Research, vol. 86, no. 5, pp. 1024–1035, 2008.
[11]
S. H. Chen, F. M. Chang, Y. C. Tsai, K. F. Huang, C. L. Lin, and M. T. Lin, “Infusion of human umbilical cord blood cells protect against cerebral ischemia and damage during heatstroke in the rat,” Experimental Neurology, vol. 199, no. 1, pp. 67–76, 2006.
[12]
D. J. Prockop, C. A. Gregory, and J. L. Spees, “One strategy for cell and gene therapy: Harnessing the power of adult stem cells to repair tissues,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, supplement 1, pp. 11917–11923, 2003.
[13]
F. Benedetti, “The CD34+ cell: biological aspects,” Tumori, vol. 82, no. 2, pp. S3–S13, 1996.
[14]
A. Taguchi, T. Soma, H. Tanaka et al., “Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model,” The Journal of Clinical Investigation, vol. 114, no. 3, pp. 330–338, 2004.
[15]
W.-C. Shyu, S.-Z. Lin, M.-F. Chiang, C.-Y. Su, and H. Li, “Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing β1 integrin-mediated angiogenesis in chronic stroke rats,” Journal of Neuroscience, vol. 26, no. 13, pp. 3444–3453, 2006.
[16]
A. Taguchi, “Cell-based therapy for patients with vascular dementia,” Psychogeriatrics, vol. 11, no. 2, pp. 113–115, 2011.
[17]
A. Taguchi, T. Matsuyama, T. Nakagomi et al., “Circulating CD34-positive cells provide a marker of vascular risk associated with cognitive impairment,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 3, pp. 445–449, 2008.
[18]
A. Taguchi, T. Matsuyama, H. Moriwaki et al., “Circulating CD34-positive cells provide an index of cerebrovascular function,” Circulation, vol. 109, no. 24, pp. 2972–2975, 2004.
[19]
A. R. Mackie and D. W. Losordo, “CD34-positive stem cells: in the treatment of Heart and vascular disease in human beings,” Texas Heart Institute Journal, vol. 38, no. 5, pp. 474–485, 2011.
[20]
S. I. Savitz, M. Chopp, R. Deans, S. T. Carmichael, D. Phinney, and L. Wechsler, “Stem cell therapy as an emerging paradigm for stroke (STEPS) II,” Stroke, vol. 42, no. 3, pp. 825–829, 2011.
[21]
L. R. Wechsler, “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, vol. 40, no. 2, pp. 510–515, 2009.
[22]
A. Marabelle, E. Merlin, P. Halle et al., “CD34+ immunoselection of autologous grafts for the treatment of high-risk neuroblastoma,” Pediatric Blood and Cancer, vol. 56, no. 1, pp. 134–142, 2011.
[23]
M. Kinoshita, Y. Fujita, M. Katayama, et al., “Long-term clinical outcome after intramuscular transplantation of granulocyte colony stimulating factor-mobilized CD34 positive cells in patients with critical limb ischemia,” Atherosclerosis, vol. 224, pp. 440–445, 2012.
[24]
C. G. Begley, A. F. Lopez, and N. A. Nicola, “Purified colony-stimulating factors enhance the survival of human neutrophils and eosinophils in vitro: a rapid and sensitive microassay for colony-stimulating factors,” Blood, vol. 68, no. 1, pp. 162–166, 1986.
[25]
D. Metcalf, “The colony stimulating factors. Discovery, development, and clinical applications,” Cancer, vol. 65, pp. 2185–2195, 1990.
[26]
Y. Sehara, T. Hayashi, K. Deguchi et al., “Decreased focal inflammatory response by G-CSF may improve stroke outcome after transient middle cerebral artery occlusion in rats,” Journal of Neuroscience Research, vol. 85, no. 10, pp. 2167–2174, 2007.
[27]
Y. Sehara, T. Hayashi, K. Deguchi et al., “Potentiation of neurogenesis and angiogenesis by G-CSF after focal cerebral ischemia in rats,” Brain Research, vol. 1151, no. 1, pp. 142–149, 2007.
[28]
A. M. Cavallaro, K. Lilleby, I. Majolino et al., “Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor,” Bone Marrow Transplantation, vol. 25, no. 1, pp. 85–89, 2000.
[29]
S. Boy, S. Sauerbruch, M. Kraemer, et al., “Mobilisation of hematopoietic CD34+ precursor cells in patients with acute stroke is safe—results of an open-labeled non randomized phase I/II trial,” PLoS ONE, vol. 6, no. 8, Article ID e23099, 2011.
[30]
N. Sprigg, P. M. Bath, L. Zhao et al., “Granulocyte-colony—stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092),” Stroke, vol. 37, no. 12, pp. 2979–2983, 2006.
[31]
T. J. England, M. Abaei, D. P. Auer et al., “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, vol. 43, no. 2, pp. 405–411, 2012.
[32]
T. Mehta, A. Feroz, U. Thakkar, A. Vanikar, V. Shah, and H. Trivedi, “Subarachnoid placement of stem cells in neurological disorders,” Transplantation Proceedings, vol. 40, no. 4, pp. 1145–1147, 2008.
[33]
W.-Z. Yang, Y. Zhang, F. Wu et al., “Human umbilical cord blood-derived mononuclear cell transplantation: case series of 30 subjects with Hereditary Ataxia,” Journal of Translational Medicine, vol. 9, article 65, 2011.
[34]
B. Hennemann, G. W. Ickenstein, S. Sauerbruch et al., “Mobilization of CD34+ hematopoietic cells, colony-forming cells and long-term cultureinitiating cells into the peripheral blood of patients with an acute cerebral ischemic insult,” Cytotherapy, vol. 10, no. 3, pp. 303–311, 2008.
[35]
M. Majka, A. Janowska-Wieczorek, J. Ratajczak et al., “Numerous growth factors, cytokines, and chemokines are secreted by human CD34+ cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner,” Blood, vol. 97, no. 10, pp. 3075–3085, 2001.
