Cargando…

JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models

Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment m...

Descripción completa

Detalles Bibliográficos
Autores principales: Ha, Geun-Hyoung, Kim, Eun Ji, Park, Jee Soo, Kim, Ji Eun, Nam, Hyun, Yeon, Je Young, Lee, Sun-Ho, Lee, Kyunghoon, Kim, Chung Kwon, Joo, Kyeung Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740376/
https://www.ncbi.nlm.nih.gov/pubmed/36446389
http://dx.doi.org/10.18632/aging.204410
_version_ 1784848046268350464
author Ha, Geun-Hyoung
Kim, Eun Ji
Park, Jee Soo
Kim, Ji Eun
Nam, Hyun
Yeon, Je Young
Lee, Sun-Ho
Lee, Kyunghoon
Kim, Chung Kwon
Joo, Kyeung Min
author_facet Ha, Geun-Hyoung
Kim, Eun Ji
Park, Jee Soo
Kim, Ji Eun
Nam, Hyun
Yeon, Je Young
Lee, Sun-Ho
Lee, Kyunghoon
Kim, Chung Kwon
Joo, Kyeung Min
author_sort Ha, Geun-Hyoung
collection PubMed
description Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 10(5) ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.
format Online
Article
Text
id pubmed-9740376
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Impact Journals
record_format MEDLINE/PubMed
spelling pubmed-97403762022-12-12 JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models Ha, Geun-Hyoung Kim, Eun Ji Park, Jee Soo Kim, Ji Eun Nam, Hyun Yeon, Je Young Lee, Sun-Ho Lee, Kyunghoon Kim, Chung Kwon Joo, Kyeung Min Aging (Albany NY) Research Paper Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 10(5) ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke. Impact Journals 2022-11-29 /pmc/articles/PMC9740376/ /pubmed/36446389 http://dx.doi.org/10.18632/aging.204410 Text en Copyright: © 2022 Ha et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Ha, Geun-Hyoung
Kim, Eun Ji
Park, Jee Soo
Kim, Ji Eun
Nam, Hyun
Yeon, Je Young
Lee, Sun-Ho
Lee, Kyunghoon
Kim, Chung Kwon
Joo, Kyeung Min
JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
title JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
title_full JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
title_fullStr JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
title_full_unstemmed JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
title_short JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
title_sort jak2/stat3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740376/
https://www.ncbi.nlm.nih.gov/pubmed/36446389
http://dx.doi.org/10.18632/aging.204410
work_keys_str_mv AT hageunhyoung jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT kimeunji jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT parkjeesoo jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT kimjieun jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT namhyun jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT yeonjeyoung jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT leesunho jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT leekyunghoon jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT kimchungkwon jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels
AT jookyeungmin jak2stat3pathwaymediatesneuroprotectiveandproangiogenictreatmenteffectsofadulthumanneuralstemcellsinmiddlecerebralarteryocclusionstrokeanimalmodels