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Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung

Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late nor...

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Autores principales: Montay-Gruel, Pierre, Zhu, Yafeng, Petit, Benoit, Leavitt, Ron, Warn, Mike, Giedzinski, Erich, Ollivier, Jonathan, Sinclair, David A., Vozenin, Marie-Catherine, Limoli, Charles L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962869/
https://www.ncbi.nlm.nih.gov/pubmed/33738245
http://dx.doi.org/10.3389/fonc.2020.602763
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author Montay-Gruel, Pierre
Zhu, Yafeng
Petit, Benoit
Leavitt, Ron
Warn, Mike
Giedzinski, Erich
Ollivier, Jonathan
Sinclair, David A.
Vozenin, Marie-Catherine
Limoli, Charles L.
author_facet Montay-Gruel, Pierre
Zhu, Yafeng
Petit, Benoit
Leavitt, Ron
Warn, Mike
Giedzinski, Erich
Ollivier, Jonathan
Sinclair, David A.
Vozenin, Marie-Catherine
Limoli, Charles L.
author_sort Montay-Gruel, Pierre
collection PubMed
description Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure of the lung to ionizing radiation. The hESC-derived EV were systemically administered to the mice via the retro-orbital sinus to explore the potential therapeutic benefits following exposure to high thoracic doses of radiation (14 Gy). Data demonstrated that hESC-derived EV treatment significantly improved overall survival of the irradiated cohorts (P < 0.001). Increased survival was also associated with significant reductions in lung fibrosis as quantified by CBCT imaging (P < 0.01, 2 weeks post-irradiation). Qualitative histological analyses revealed reduced indications of radiation induced pulmonary injury in animals treated with EV. EV were then subjected to a rigorous proteomic analysis to ascertain the potential bioactive cargo that may prove beneficial in ameliorating radiation-induced normal tissue toxicities in the lung. Proteomics validated several consensus exosome markers (e.g., CD68) and identified major classes of proteins involved in nuclear pore complexes, epigenetics, cell cycle, growth and proliferation, DNA repair, antioxidant function, and cellular metabolism (TCA cycle and oxidative phosphorylation, OXYPHOS). Interestingly, EV were also found to contain mitochondrial components (mtDNA, OXYPHOS protein subunits), which may contribute to the metabolic reprograming and recovery of radiation-injured pulmonary tissue. To evaluate the safety of EV treatments in the context of the radiotherapeutic management of tumors, mice harboring TC1 tumor xenografts were subjected to the same EV treatments shown to forestall lung fibrosis. Data indicated that over the course of one month, no change in the growth of flank tumors between treated and control cohorts was observed. In conclusion, present findings demonstrate that systemic delivery of hESC-derived EV could ameliorate radiation-induced normal tissue complications in the lung, through a variety of potential mechanisms based on EV cargo analysis.
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spelling pubmed-79628692021-03-17 Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung Montay-Gruel, Pierre Zhu, Yafeng Petit, Benoit Leavitt, Ron Warn, Mike Giedzinski, Erich Ollivier, Jonathan Sinclair, David A. Vozenin, Marie-Catherine Limoli, Charles L. Front Oncol Oncology Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure of the lung to ionizing radiation. The hESC-derived EV were systemically administered to the mice via the retro-orbital sinus to explore the potential therapeutic benefits following exposure to high thoracic doses of radiation (14 Gy). Data demonstrated that hESC-derived EV treatment significantly improved overall survival of the irradiated cohorts (P < 0.001). Increased survival was also associated with significant reductions in lung fibrosis as quantified by CBCT imaging (P < 0.01, 2 weeks post-irradiation). Qualitative histological analyses revealed reduced indications of radiation induced pulmonary injury in animals treated with EV. EV were then subjected to a rigorous proteomic analysis to ascertain the potential bioactive cargo that may prove beneficial in ameliorating radiation-induced normal tissue toxicities in the lung. Proteomics validated several consensus exosome markers (e.g., CD68) and identified major classes of proteins involved in nuclear pore complexes, epigenetics, cell cycle, growth and proliferation, DNA repair, antioxidant function, and cellular metabolism (TCA cycle and oxidative phosphorylation, OXYPHOS). Interestingly, EV were also found to contain mitochondrial components (mtDNA, OXYPHOS protein subunits), which may contribute to the metabolic reprograming and recovery of radiation-injured pulmonary tissue. To evaluate the safety of EV treatments in the context of the radiotherapeutic management of tumors, mice harboring TC1 tumor xenografts were subjected to the same EV treatments shown to forestall lung fibrosis. Data indicated that over the course of one month, no change in the growth of flank tumors between treated and control cohorts was observed. In conclusion, present findings demonstrate that systemic delivery of hESC-derived EV could ameliorate radiation-induced normal tissue complications in the lung, through a variety of potential mechanisms based on EV cargo analysis. Frontiers Media S.A. 2021-03-02 /pmc/articles/PMC7962869/ /pubmed/33738245 http://dx.doi.org/10.3389/fonc.2020.602763 Text en Copyright © 2021 Montay-Gruel, Zhu, Petit, Leavitt, Warn, Giedzinski, Ollivier, Sinclair, Vozenin and Limoli http://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 Oncology
Montay-Gruel, Pierre
Zhu, Yafeng
Petit, Benoit
Leavitt, Ron
Warn, Mike
Giedzinski, Erich
Ollivier, Jonathan
Sinclair, David A.
Vozenin, Marie-Catherine
Limoli, Charles L.
Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
title Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
title_full Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
title_fullStr Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
title_full_unstemmed Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
title_short Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
title_sort extracellular vesicles for the treatment of radiation-induced normal tissue toxicity in the lung
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962869/
https://www.ncbi.nlm.nih.gov/pubmed/33738245
http://dx.doi.org/10.3389/fonc.2020.602763
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