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Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability

The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during sh...

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Autores principales: Do, Jeong-su, Zwick, Daniel, Kenyon, Jonathan D., Zhong, Fei, Askew, David, Huang, Alex Y., Van’t Hof, Wouter, Finney, Marcie, Laughlin, Mary J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140113/
https://www.ncbi.nlm.nih.gov/pubmed/34021231
http://dx.doi.org/10.1038/s41598-021-90115-8
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author Do, Jeong-su
Zwick, Daniel
Kenyon, Jonathan D.
Zhong, Fei
Askew, David
Huang, Alex Y.
Van’t Hof, Wouter
Finney, Marcie
Laughlin, Mary J.
author_facet Do, Jeong-su
Zwick, Daniel
Kenyon, Jonathan D.
Zhong, Fei
Askew, David
Huang, Alex Y.
Van’t Hof, Wouter
Finney, Marcie
Laughlin, Mary J.
author_sort Do, Jeong-su
collection PubMed
description The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during short-term ex vivo expansion enhances the stability of iTreg FOXP3 expression and suppressive function in vitro and in vivo, and further that a key mechanism of action is MSC mitochondrial (mt) transfer via tunneling nanotubules (TNT). MSC mt transfer is driven by mitochondrial metabolic function (CD39/CD73 signaling) in proliferating iTreg and promotes iTreg expression of FOXP3 stabilizing factors BACH2 and SENP3. These results elucidate cellular and molecular mechanisms underlying human MSC mt transfer to proliferating cells. MSC mt transfer stabilizes FOXP3 expression in iTregs, thereby enhancing and sustaining their suppressive function in inflammatory conditions in vitro and in vivo.
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spelling pubmed-81401132021-05-25 Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability Do, Jeong-su Zwick, Daniel Kenyon, Jonathan D. Zhong, Fei Askew, David Huang, Alex Y. Van’t Hof, Wouter Finney, Marcie Laughlin, Mary J. Sci Rep Article The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during short-term ex vivo expansion enhances the stability of iTreg FOXP3 expression and suppressive function in vitro and in vivo, and further that a key mechanism of action is MSC mitochondrial (mt) transfer via tunneling nanotubules (TNT). MSC mt transfer is driven by mitochondrial metabolic function (CD39/CD73 signaling) in proliferating iTreg and promotes iTreg expression of FOXP3 stabilizing factors BACH2 and SENP3. These results elucidate cellular and molecular mechanisms underlying human MSC mt transfer to proliferating cells. MSC mt transfer stabilizes FOXP3 expression in iTregs, thereby enhancing and sustaining their suppressive function in inflammatory conditions in vitro and in vivo. Nature Publishing Group UK 2021-05-21 /pmc/articles/PMC8140113/ /pubmed/34021231 http://dx.doi.org/10.1038/s41598-021-90115-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Do, Jeong-su
Zwick, Daniel
Kenyon, Jonathan D.
Zhong, Fei
Askew, David
Huang, Alex Y.
Van’t Hof, Wouter
Finney, Marcie
Laughlin, Mary J.
Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
title Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
title_full Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
title_fullStr Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
title_full_unstemmed Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
title_short Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
title_sort mesenchymal stromal cell mitochondrial transfer to human induced t-regulatory cells mediates foxp3 stability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140113/
https://www.ncbi.nlm.nih.gov/pubmed/34021231
http://dx.doi.org/10.1038/s41598-021-90115-8
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