Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice
Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of...
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Neurology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fneur.2018.00133/full |
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| author | Emi Tanaka Emi Tanaka Yuko Ogawa Takeo Mukai Yoshiaki Sato Takashi Hamazaki Tokiko Nagamura-Inoue Mariko Harada-Shiba Haruo Shintaku Masahiro Tsuji |
| author_facet | Emi Tanaka Emi Tanaka Yuko Ogawa Takeo Mukai Yoshiaki Sato Takashi Hamazaki Tokiko Nagamura-Inoue Mariko Harada-Shiba Haruo Shintaku Masahiro Tsuji |
| author_sort | Emi Tanaka |
| collection | DOAJ |
| description | Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating the microglial reaction in the peri-infarct cortex. |
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| id | doaj.art-a13c33a5ef0244e7b58623ea9122b2aa |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-12T16:18:02Z |
| publishDate | 2018-03-01 |
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| series | Frontiers in Neurology |
| spelling | doaj.art-a13c33a5ef0244e7b58623ea9122b2aa2022-12-22T00:19:02ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-03-01910.3389/fneur.2018.00133345800Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke MiceEmi Tanaka0Emi Tanaka1Yuko Ogawa2Takeo Mukai3Yoshiaki Sato4Takashi Hamazaki5Tokiko Nagamura-Inoue6Mariko Harada-Shiba7Haruo Shintaku8Masahiro Tsuji9Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, JapanDepartment of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, JapanDepartment of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, JapanDepartment of Cell Processing and Transfusion, Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, JapanDepartment of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, JapanDepartment of Cell Processing and Transfusion, Institute of Medical Science, The University of Tokyo, Tokyo, JapanDepartment of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, JapanDepartment of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, JapanDepartment of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, JapanNeonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating the microglial reaction in the peri-infarct cortex.http://journal.frontiersin.org/article/10.3389/fneur.2018.00133/fullmesenchymal stem cellumbilical cord-derived mesenchymal stem cellneonatal strokeneonatal brain injuryintravenous administration |
| spellingShingle | Emi Tanaka Emi Tanaka Yuko Ogawa Takeo Mukai Yoshiaki Sato Takashi Hamazaki Tokiko Nagamura-Inoue Mariko Harada-Shiba Haruo Shintaku Masahiro Tsuji Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice Frontiers in Neurology mesenchymal stem cell umbilical cord-derived mesenchymal stem cell neonatal stroke neonatal brain injury intravenous administration |
| title | Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice |
| title_full | Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice |
| title_fullStr | Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice |
| title_full_unstemmed | Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice |
| title_short | Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice |
| title_sort | dose dependent effect of intravenous administration of human umbilical cord derived mesenchymal stem cells in neonatal stroke mice |
| topic | mesenchymal stem cell umbilical cord-derived mesenchymal stem cell neonatal stroke neonatal brain injury intravenous administration |
| url | http://journal.frontiersin.org/article/10.3389/fneur.2018.00133/full |
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