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      Combining Human Umbilical Cord Blood Cells With Erythropoietin Enhances Angiogenesis/Neurogenesis and Behavioral Recovery After Stroke

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          Abstract

          Disruption of blood flow in the brain induces stroke, the leading cause of death and disability worldwide. However, so far the therapeutic options are limited. Thus, the therapeutic efficacy of cell-based approaches has been investigated to develop a potential strategy to overcome stroke-induced disability. Human umbilical cord blood cells (hUCBCs) and erythropoietin (EPO) both have angiogenic and neurogenic properties in the injured brain, and their combined administration may exert synergistic effects during neurological recovery following stroke. We investigated the therapeutic potential of hUCBC and EPO combination treatment by comparing its efficacy to those of hUCBC and EPO alone. Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion (MCAO). Experimental groups were as follows: saline (injected once with saline 7 d after MCAO); hUCBC (1.2 × 10 7 total nucleated cells, injected once via the tail vein 7 d after MCAO); EPO (500 IU/kg, injected intraperitoneally for five consecutive days from 7 d after MCAO); and combination of hUCBC and EPO (hUCBC+EPO). Behavioral measures (Modified Neurological Severity Score [mNSS] and cylinder test) were recorded to assess neurological outcomes. Four weeks after MCAO, brains were harvested to analyze the status of neurogenesis and angiogenesis. In vitro assays were also conducted using neural stem and endothelial cells in the oxygen-glucose deprivation condition. Performance on the mNSS and cylinder test showed the most improvement in the hUCBC+EPO group, while hUCBC- and EPO-alone treatments showed superior outcomes relative to the saline group. Neurogenesis and angiogenesis in the cortical region was the most enhanced in the hUCBC+EPO group, while the findings in the hUCBC and EPO treatment alone groups were better than those in the saline group. Astrogliosis in the brain tissue was reduced by hUCBC and EPO treatment. The reduction was largest in the hUCBC+EPO group. These results were consistent with in vitro assessments that showed the strongest neurogenic and angiogenic effect with hUCBC+EPO treatment. This study demonstrates that combination therapy is more effective than single therapy with either hUCBC or EPO for neurological recovery from subacute stroke. The common pathway underlying hUCBC and EPO treatment requires further study.

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          Most cited references 43

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          Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats.

          Human umbilical cord blood cells (HUCBC) are rich in stem and progenitor cells. In this study we tested whether intravenously infused HUCBC enter brain, survive, differentiate, and improve neurological functional recovery after stroke in rats. In addition, we tested whether ischemic brain tissue extract selectively induces chemotaxis of HUCBC in vitro. Adult male Wistar rats were subjected to transient (2-hour) middle cerebral artery occlusion (MCAO). Experimental groups were as follows: group 1, MCAO alone (n=5); group 2, 3x10(6) HUCBC injected into tail vein at 24 hours after MCAO (n=6) (animals of groups 1 and 2 were killed at 14 days after MCAO); group 3, MCAO alone (n=5); group 4, MCAO injected with PBS at 1 day after stroke (n=8); and group 5, 3x10(6) HUCBC injected into tail vein at 7 days after MCAO (n=5). Rats of groups 3, 4, and 5 were killed at 35 days after MCAO. Behavioral tests (rotarod and Modified Neurological Severity Score [mNSS]) were performed. Immunohistochemical staining was used to identify cells derived from HUCBC. Chemotactic activity of ischemia brain tissue extracts toward HUCBC at different time points was evaluated in vitro. Treatment at 24 hours after MCAO with HUCBC significantly improved functional recovery, as evidenced by the rotarod test and mNSS (P<0.05). Treatment at 7 days after MCAO with HUCBC significantly improved function only on the mNSS (P<0.05). Some HUCBC were reactive for the astrocyte marker glial fibrillary acidic protein and the neuronal markers NeuN and microtubule-associated protein 2. In vitro, significant HUCBC migration activity was present at 24 hours after MCAO (P<0.01) compared with normal brain tissue. Intravenously administered HUCBC enter brain, survive, migrate, and improve functional recovery after stroke. HUCBC transplantation may provide a cell source to treat stroke.
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            Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats.

            Erythropoietin (EPO) promotes proliferation and differentiation of erythroid progenitors and the survival of maturing erythroid cells. Here, we investigated the role of EPO in brain repair after stroke. Rats were treated with recombinant human EPO (rhEPO) at 24 hours after the onset of embolic stroke. An array of behavior tests was performed. Rats were euthanized 28 days after stroke for measurements of infarct volume, angiogenesis, and neurogenesis. In vitro, neurospheres derived from the subventricular zone (SVZ) of the rat and cerebral endothelial cells derived from the mouse were treated with rhEPO. Capillary-like tube formation and neuronal differentiation were measured. Treatment with rhEPO significantly improved functional recovery, along with increases in density of cerebral microvessels at the stroke boundary and numbers of BrdU, doublecortin, and nestin immunoreactive cells in the SVZ. rhEPO treatment significantly increased brain levels of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). In vitro, rhEPO enhanced capillary tube formation of cerebral endothelial cells, which was inhibited by a specific VEGF receptor 2 antagonist (SU1498). Incubation of neurospheres derived from stroke SVZ with anti-EPO neutralizing antibody inhibited neurogenesis, whereas incubation of stroke-derived neurospheres with rhEPO enhanced neurogenesis. Our data suggest that EPO-increased VEGF and BDNF may be involved in angiogenesis and neurogenesis, which could contribute to functional recovery.
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              Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats

               J. Chen,  L. Wang,  Y. Li (2001)
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                10 April 2019
                2019
                : 10
                Affiliations
                1Rehabilitation and Regeneration Research Center, CHA University , Seongnam, South Korea
                2Department of Rehabilitation Medicine, CHA Bundang Medical Center, College of Medicine, CHA University , Seongnam, South Korea
                Author notes

                Edited by: Paulo Henrique Rosado-de-Castro, Instituto D'Or de Pesquisa e Ensino (IDOR), Brazil

                Reviewed by: Samuel Greggio, Institute of the Brain of Rio Grande do Sul (InsCer), Brazil; Bharath Chelluboina, University of Wisconsin-Madison, United States

                *Correspondence: MinYoung Kim kmin@ 123456cha.ac.kr

                This article was submitted to Stroke, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2019.00357
                6467968
                Copyright © 2019 Hwang, Choi and Kim.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 46, Pages: 15, Words: 7958
                Funding
                Funded by: Ministry of Trade, Industry and Energy 10.13039/501100003052
                Award ID: 10051152
                Categories
                Neurology
                Original Research

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