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Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke

We recently demonstrated that injury/ischemia-induced multipotent stem cells (iSCs) develop within post-stroke human brains. Because iSCs are stem cells induced under pathological conditions, such as ischemic stroke, the use of human brain-derived iSCs (h-iSCs) may represent a novel therapy for stro...

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Autores principales: Nakagomi, Takayuki, Nakano-Doi, Akiko, Kubo, Shuji, Sawano, Toshinori, Kuramoto, Yoji, Yamahara, Kenichi, Matsuyama, Tomohiro, Takagi, Toshinori, Doe, Nobutaka, Yoshimura, Shinichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267578/
https://www.ncbi.nlm.nih.gov/pubmed/37221140
http://dx.doi.org/10.1093/stcltm/szad031
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author Nakagomi, Takayuki
Nakano-Doi, Akiko
Kubo, Shuji
Sawano, Toshinori
Kuramoto, Yoji
Yamahara, Kenichi
Matsuyama, Tomohiro
Takagi, Toshinori
Doe, Nobutaka
Yoshimura, Shinichi
author_facet Nakagomi, Takayuki
Nakano-Doi, Akiko
Kubo, Shuji
Sawano, Toshinori
Kuramoto, Yoji
Yamahara, Kenichi
Matsuyama, Tomohiro
Takagi, Toshinori
Doe, Nobutaka
Yoshimura, Shinichi
author_sort Nakagomi, Takayuki
collection PubMed
description We recently demonstrated that injury/ischemia-induced multipotent stem cells (iSCs) develop within post-stroke human brains. Because iSCs are stem cells induced under pathological conditions, such as ischemic stroke, the use of human brain-derived iSCs (h-iSCs) may represent a novel therapy for stroke patients. We performed a preclinical study by transplanting h-iSCs transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion (MCAO). Compared with PBS-treated controls, h-iSC transplantation significantly improved neurological function. To identify the underlying mechanism, green fluorescent protein (GFP)-labeled h-iSCs were transplanted into post-stroke mouse brains. Immunohistochemistry revealed that GFP(+) h-iSCs survived around the ischemic areas and some differentiated into mature neuronal cells. To determine the effect on endogenous neural stem/progenitor cells (NSPCs) by h-iSC transplantation, mCherry-labeled h-iSCs were administered to Nestin-GFP transgenic mice which were subjected to MCAO. As a result, many GFP(+) NSPCs were observed around the injured sites compared with controls, indicating that mCherry(+) h-iSCs activate GFP(+) endogenous NSPCs. In support of these findings, coculture studies revealed that the presence of h-iSCs promotes the proliferation of endogenous NSPCs and increases neurogenesis. In addition, coculture experiments indicated neuronal network formation between h-iSC- and NSPC-derived neurons. These results suggest that h-iSCs exert positive effects on neural regeneration through not only neural replacement by grafted cells but also neurogenesis by activated endogenous NSPCs. Thus, h-iSCs have the potential to be a novel source of cell therapy for stroke patients.
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spelling pubmed-102675782023-06-15 Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke Nakagomi, Takayuki Nakano-Doi, Akiko Kubo, Shuji Sawano, Toshinori Kuramoto, Yoji Yamahara, Kenichi Matsuyama, Tomohiro Takagi, Toshinori Doe, Nobutaka Yoshimura, Shinichi Stem Cells Transl Med Tissue Engineering and Regenerative Medicine We recently demonstrated that injury/ischemia-induced multipotent stem cells (iSCs) develop within post-stroke human brains. Because iSCs are stem cells induced under pathological conditions, such as ischemic stroke, the use of human brain-derived iSCs (h-iSCs) may represent a novel therapy for stroke patients. We performed a preclinical study by transplanting h-iSCs transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion (MCAO). Compared with PBS-treated controls, h-iSC transplantation significantly improved neurological function. To identify the underlying mechanism, green fluorescent protein (GFP)-labeled h-iSCs were transplanted into post-stroke mouse brains. Immunohistochemistry revealed that GFP(+) h-iSCs survived around the ischemic areas and some differentiated into mature neuronal cells. To determine the effect on endogenous neural stem/progenitor cells (NSPCs) by h-iSC transplantation, mCherry-labeled h-iSCs were administered to Nestin-GFP transgenic mice which were subjected to MCAO. As a result, many GFP(+) NSPCs were observed around the injured sites compared with controls, indicating that mCherry(+) h-iSCs activate GFP(+) endogenous NSPCs. In support of these findings, coculture studies revealed that the presence of h-iSCs promotes the proliferation of endogenous NSPCs and increases neurogenesis. In addition, coculture experiments indicated neuronal network formation between h-iSC- and NSPC-derived neurons. These results suggest that h-iSCs exert positive effects on neural regeneration through not only neural replacement by grafted cells but also neurogenesis by activated endogenous NSPCs. Thus, h-iSCs have the potential to be a novel source of cell therapy for stroke patients. Oxford University Press 2023-05-23 /pmc/articles/PMC10267578/ /pubmed/37221140 http://dx.doi.org/10.1093/stcltm/szad031 Text en © The Author(s) 2023. Published by Oxford University Press. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
spellingShingle Tissue Engineering and Regenerative Medicine
Nakagomi, Takayuki
Nakano-Doi, Akiko
Kubo, Shuji
Sawano, Toshinori
Kuramoto, Yoji
Yamahara, Kenichi
Matsuyama, Tomohiro
Takagi, Toshinori
Doe, Nobutaka
Yoshimura, Shinichi
Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke
title Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke
title_full Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke
title_fullStr Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke
title_full_unstemmed Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke
title_short Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke
title_sort transplantation of human brain-derived ischemia-induced multipotent stem cells ameliorates neurological dysfunction in mice after stroke
topic Tissue Engineering and Regenerative Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267578/
https://www.ncbi.nlm.nih.gov/pubmed/37221140
http://dx.doi.org/10.1093/stcltm/szad031
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