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

Abstract 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)...

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Autores principales:	Jeong-su Do, Daniel Zwick, Jonathan D. Kenyon, Fei Zhong, David Askew, Alex Y. Huang, Wouter Van’t Hof, Marcie Finney, Mary J. Laughlin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/24468a2c65444254ba3db5b26d183319
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spelling	oai:doaj.org-article:24468a2c65444254ba3db5b26d1833192021-12-02T16:49:37ZMesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability10.1038/s41598-021-90115-82045-2322https://doaj.org/article/24468a2c65444254ba3db5b26d1833192021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90115-8https://doaj.org/toc/2045-2322Abstract 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.Jeong-su DoDaniel ZwickJonathan D. KenyonFei ZhongDavid AskewAlex Y. HuangWouter Van’t HofMarcie FinneyMary J. LaughlinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jeong-su Do Daniel Zwick Jonathan D. Kenyon Fei Zhong David Askew Alex Y. Huang Wouter Van’t Hof Marcie Finney Mary J. Laughlin Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
description	Abstract 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.
format	article
author	Jeong-su Do Daniel Zwick Jonathan D. Kenyon Fei Zhong David Askew Alex Y. Huang Wouter Van’t Hof Marcie Finney Mary J. Laughlin
author_facet	Jeong-su Do Daniel Zwick Jonathan D. Kenyon Fei Zhong David Askew Alex Y. Huang Wouter Van’t Hof Marcie Finney Mary J. Laughlin
author_sort	Jeong-su Do
title	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_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_sort	mesenchymal stromal cell mitochondrial transfer to human induced t-regulatory cells mediates foxp3 stability
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/24468a2c65444254ba3db5b26d183319
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Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability

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