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      Optimal Route for Mesenchymal Stem Cells Transplantation after Severe Intraventricular Hemorrhage in Newborn Rats

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          Abstract

          Recently, we showed that intracerebroventricular (IC) transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuates posthemorrhagic hydrocephalus (PHH) and brain damage after severe IVH in newborn rats. This study was performed to determine the optimal route for transplanting MSCs for severe IVH by comparing IC transplantation, intravenous (IV) transplantation, and IV transplantation plus mannitol infusion. Severe IVH was induced by injecting 100 uL of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). After confirming severe IVH with brain magnetic resonance imaging (MRI) at P5, human UCB-derived MSCs were transplanted at P6 by an IC route (1×10 5), an IV route (5×10 5), or an IV route with mannitol infused. Follow-up brain MRIs and rotarod tests were performed. At P32, brain tissue samples were obtained for biochemical and histological analyses. Although more MSCs localized to the brain after IC than after IV delivery, both methods were equally effective in preventing PHH; attenuating impaired rotarod test; increasing the number of TUNEL-positive cells, inflammatory cytokines, and astrogliosis; and reducing corpus callosal thickness and myelin basic protein expression after severe IVH regardless of mannitol co-infusion. Despite the superior delivery efficacy with IC than with the IV route, both IC and IV transplantation of MSCs had equal therapeutic efficacy in protecting against severe IVH. These findings suggest that the less invasive IV route might be a good alternative for clinically unstable, very preterm infants that cannot tolerate a more invasive IC delivery of MSCs.

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          Most cited references 40

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          Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.

          We have performed brain scanning by computed tomography on 46 consecutive live-born infants whose birth weights were less than 1,500 gm; 20 of them had evidence of cerebral intraventricular hemorrhage. Nine of the 29 infants who survived had IVH. Four grades of IVH were identified. Grade I and II lesions resolved spontaneously, but there was prominence of the interhemispheric fissue on CT of the infants at six months of age. Hydrocephalus developed in infants with Grade III and IV lesions. Seven of the surviving infants with IVH did not have clinical evidence of hemorrhage. There were no significant differences between the infants with and without IVH in birth weight, gestational age, one- and five-minute Apgar scores, or the need for resuscitation at birth or for subsequent respiratory assistance.
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            Mesenchymal stem cells secrete immunologically active exosomes.

            Mesenchymal stem cells (MSCs) have been shown to secrete exosomes that are cardioprotective. Here, we demonstrated that MSC exosome, a secreted membrane vesicle, is immunologically active. MSC exosomes induced polymyxin-resistant, MYD88-dependent secreted embryonic alkaline phosphatase (SEAP) expression in a THP1-Xblue, a THP-1 reporter cell line with an NFκB-SEAP reporter gene. In contrast to lipopolysaccharide, they induced high levels of anti-inflammatory IL10 and TGFβ1 transcript at 3 and 72 h, and much attenuated levels of pro-inflammatory IL1B, IL6, TNFA and IL12P40 transcript at 3-h. The 3-h but not 72-h induction of cytokine transcript was abrogated by MyD88 deficiency. Primary human and mouse monocytes exhibited a similar exosome-induced cytokine transcript profile. Exosome-treated THP-1 but not MyD88-deficient THP-1 cells polarized activated CD4(+) T cells to CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) at a ratio of one exosome-treated THP-1 cell to 1,000 CD4(+) T cells. Infusion of MSC exosomes enhanced the survival of allogenic skin graft in mice and increased Tregs.
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              Regulatory networks in embryo-derived pluripotent stem cells.

              Mammalian development requires the specification of over 200 cell types from a single totipotent cell. Investigation of the regulatory networks that are responsible for pluripotency in embryo-derived stem cells is fundamental to understanding mammalian development and realizing therapeutic potential. Extracellular signals and second messengers modulate cell-autonomous regulators such as OCT4, SOX2 and Nanog in a combinatorial complexity. Knowledge of this circuitry might reveal how to achieve phenotypic changes without the genetic manipulation of Oct4, Nanog and other toti/pluripotency-associated genes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 July 2015
                2015
                : 10
                : 7
                Affiliations
                [1 ]Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [2 ]Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [3 ]Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul, Korea
                Rutgers - New Jersey Medical School, UNITED STATES
                Author notes

                Competing Interests: Soo Jin Choi is an employee of MEDIPOST Co., Ltd. MEDIPOST Co., Ltd. provided support in the form of a salary for author SJC, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Won Soon Park and Yun Sil Chang declare potential conflicts of interest arising from a filed or issued patent titled “Composition for treating intraventricular hemorrhage in preterm infants comprising mesenchymal stem cells” (filed or issued number:13/655,356 in USA and 1405620 in South Korea) as co-inventors, not as patentees. Geun Ho Im is an employee from the Samsung Biomedical Research Institute (SBRI) which is independent academic institution and is not controlled by or answerable to the commercial company known as Samsung Corporation. Samsung Medical Center is public utility foundation and also administratively separate from the Samsung Corporation. There are no additional patents, products in development or marketed products to declare. These do not alter our adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: SYA YSC DKS HSY SIS GHI SJC WSP. Performed the experiments: SYA DKS HSY SIS GHI. Analyzed the data: SYA YSC HSY SIS GHI WSP. Contributed reagents/materials/analysis tools: SJC GHI. Wrote the paper: SYA YSC DKS SIS HSY SJC GHI WSP. Supported cells: SJC. Revised and approved the manuscript: SYA YSC DKS HSY SIS GHI SJC WSP.

                [¤a]

                Current address: Department of Pediatrics, Sungkyunkwan University School of Medicine, Seoul, Korea

                [¤b]

                Current address: Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

                [¤c]

                Current address: Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul, Korea

                Article
                PONE-D-15-04459
                10.1371/journal.pone.0132919
                4514759
                26208299

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 6, Tables: 0, Pages: 14
                Product
                Funding
                This work was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (Number; A110445, Author; Won Soon Park) ( https://www.htdream.kr/) and by a Samsung Biomedical Research Institute grant (Number; SMX1131761, Author; Won Soon Park, SMX1132321, Author; So Yoon Ahn) ( http://www.skkusm.ac.kr/academics/ri.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript and do not alter our adherence to all the PLOS ONE policies on sharing data and materials.
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                All relevant data are within the paper and its Supporting Information files.

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