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ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke

Background: The transfer of mitochondria from healthy mesenchymal stem cells (MSCs) to injured MSCs has been shown to have potential therapeutic benefits for neural cell post-ischemic stroke. Specifically, functional mitochondria can perform their normal functions after being internalized by stresse...

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Autores principales: Li, Yanjiao, Wang, Yachao, Yang, Weiqi, Wu, Zhen, Ma, Daiping, Sun, Jianxiu, Tao, Huixian, Ye, Qinlian, Liu, Jingnan, Ma, Zhaoxia, Qiu, Lihua, Li, Weiping, Li, Liyan, Hu, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350566/
https://www.ncbi.nlm.nih.gov/pubmed/37465011
http://dx.doi.org/10.3389/fcell.2023.1207748
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author Li, Yanjiao
Wang, Yachao
Yang, Weiqi
Wu, Zhen
Ma, Daiping
Sun, Jianxiu
Tao, Huixian
Ye, Qinlian
Liu, Jingnan
Ma, Zhaoxia
Qiu, Lihua
Li, Weiping
Li, Liyan
Hu, Min
author_facet Li, Yanjiao
Wang, Yachao
Yang, Weiqi
Wu, Zhen
Ma, Daiping
Sun, Jianxiu
Tao, Huixian
Ye, Qinlian
Liu, Jingnan
Ma, Zhaoxia
Qiu, Lihua
Li, Weiping
Li, Liyan
Hu, Min
author_sort Li, Yanjiao
collection PubMed
description Background: The transfer of mitochondria from healthy mesenchymal stem cells (MSCs) to injured MSCs has been shown to have potential therapeutic benefits for neural cell post-ischemic stroke. Specifically, functional mitochondria can perform their normal functions after being internalized by stressed cells, leading to host cell survival. However, while this approach shows promise, there is still a lack of understanding regarding which neural cells can internalize functional mitochondria and the regulatory mechanisms involved. To address this gap, we investigated the ability of different neural cells to internalize exogenous functional mitochondria extracted from MSCs. Methods: Functional mitochondria (F-Mito) isolated from umbilical cord derived-MSCs (UCMSCs) were labeled with lentivirus of HBLV-mito-dsred-Null-PURO vector. The ability of stressed cells to internalize F-Mito was analyzed using a mouse (C57BL/6 J) middle cerebral artery occlusion (MCAO) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model. The cell viability was measured by CCK-8 kit. Time-course of intracellular ROS levels in stressed cells were analyzed by DCFH-DA staining after OGD/R and F-Mito treatment. MitoSOX, Mitotracker and WGA labeling were used to assess the relationship between ROS levels and the uptake of F-Mito at the single-cell level. Pharmacological modulation of ROS was performed using acetylcysteine (ROS inhibitor). Results: Our findings demonstrate that neurons and endothelial cells are more effective at internalizing mitochondria than astrocytes, both in vitro and in vivo, using an ischemia-reperfusion model. Additionally, internalized F-Mito decreases host cell reactive oxygen species (ROS) levels and rescues survival. Importantly, we found that the ROS response in stressed cells after ischemia is a crucial determinant in positively mediating the internalization of F-Mito by host cells, and inhibiting the generation of ROS chemicals in host cells may decrease the internalization of F-Mito. These results offer insight into how exogenous mitochondria rescue neural cells via ROS response in an ischemic stroke model. Overall, our study provides solid evidence for the translational application of MSC-derived mitochondria as a promising treatment for ischemic stroke.
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spelling pubmed-103505662023-07-18 ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke Li, Yanjiao Wang, Yachao Yang, Weiqi Wu, Zhen Ma, Daiping Sun, Jianxiu Tao, Huixian Ye, Qinlian Liu, Jingnan Ma, Zhaoxia Qiu, Lihua Li, Weiping Li, Liyan Hu, Min Front Cell Dev Biol Cell and Developmental Biology Background: The transfer of mitochondria from healthy mesenchymal stem cells (MSCs) to injured MSCs has been shown to have potential therapeutic benefits for neural cell post-ischemic stroke. Specifically, functional mitochondria can perform their normal functions after being internalized by stressed cells, leading to host cell survival. However, while this approach shows promise, there is still a lack of understanding regarding which neural cells can internalize functional mitochondria and the regulatory mechanisms involved. To address this gap, we investigated the ability of different neural cells to internalize exogenous functional mitochondria extracted from MSCs. Methods: Functional mitochondria (F-Mito) isolated from umbilical cord derived-MSCs (UCMSCs) were labeled with lentivirus of HBLV-mito-dsred-Null-PURO vector. The ability of stressed cells to internalize F-Mito was analyzed using a mouse (C57BL/6 J) middle cerebral artery occlusion (MCAO) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model. The cell viability was measured by CCK-8 kit. Time-course of intracellular ROS levels in stressed cells were analyzed by DCFH-DA staining after OGD/R and F-Mito treatment. MitoSOX, Mitotracker and WGA labeling were used to assess the relationship between ROS levels and the uptake of F-Mito at the single-cell level. Pharmacological modulation of ROS was performed using acetylcysteine (ROS inhibitor). Results: Our findings demonstrate that neurons and endothelial cells are more effective at internalizing mitochondria than astrocytes, both in vitro and in vivo, using an ischemia-reperfusion model. Additionally, internalized F-Mito decreases host cell reactive oxygen species (ROS) levels and rescues survival. Importantly, we found that the ROS response in stressed cells after ischemia is a crucial determinant in positively mediating the internalization of F-Mito by host cells, and inhibiting the generation of ROS chemicals in host cells may decrease the internalization of F-Mito. These results offer insight into how exogenous mitochondria rescue neural cells via ROS response in an ischemic stroke model. Overall, our study provides solid evidence for the translational application of MSC-derived mitochondria as a promising treatment for ischemic stroke. Frontiers Media S.A. 2023-07-03 /pmc/articles/PMC10350566/ /pubmed/37465011 http://dx.doi.org/10.3389/fcell.2023.1207748 Text en Copyright © 2023 Li, Wang, Yang, Wu, Ma, Sun, Tao, Ye, Liu, Ma, Qiu, Li, Li and Hu. https://creativecommons.org/licenses/by/4.0/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.
spellingShingle Cell and Developmental Biology
Li, Yanjiao
Wang, Yachao
Yang, Weiqi
Wu, Zhen
Ma, Daiping
Sun, Jianxiu
Tao, Huixian
Ye, Qinlian
Liu, Jingnan
Ma, Zhaoxia
Qiu, Lihua
Li, Weiping
Li, Liyan
Hu, Min
ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
title ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
title_full ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
title_fullStr ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
title_full_unstemmed ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
title_short ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
title_sort ros-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350566/
https://www.ncbi.nlm.nih.gov/pubmed/37465011
http://dx.doi.org/10.3389/fcell.2023.1207748
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