Abstract

Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune-mediated diseases. They exert immunoregulatory and tissue-restoring effects. MSC-mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose-dependent MitoT from mitochondria-labeled MSCs mainly to CD4+ T cells, rather than CD8+ T cells or CD19+ B cells. Artificial transfer of isolated MSC-derived mitochondria increases the expression of mRNA transcripts involved in T-cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFβ1, leading to an increase in a highly suppressive CD25+FoxP3+ population. In a GVHD mouse model, transplantation of MitoT-induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4+, CD8+, and IFN-γ+ expressing cell infiltration. These findings point to a unique CD4+ T-cell reprogramming mechanism with pre-clinical proof-of-concept data that pave the way for the exploration of organelle-based therapies in immune diseases.

Original languageEnglish
Article numbere48052
JournalEMBO Reports
Volume21
Issue number2
DOIs
StatePublished - 5 Feb 2020

Bibliographical note

Funding Information:
The authors would like to specially thank Andres Caicedo (Universidad San Francisco de Quito) for scientific assistance regarding the Mitoception protocol, Alex Cabrera, Hector Andr?s Ramirez, and Yessia Hidalgo (C4C-Regenero Flow Cytometry Facility) for assistance with flow cytometry and cell sorting, Macarena Oca?a and Claudia Rub? (C4C-Regenero Animal Facility) for technical expertise and assistance in the in?vivo experiments, ?lvaro Elorza (Universidad Andr?s Bello) for Seahorse services, and also the members of the C4C laboratory for support and helpful discussion. This work was supported by grants from National Agency for Investigation and Development: ANID (Agencia Nacional de Investigaci?n y Desarrollo) previously branded as the Chilean National Commission for Scientific and Technological Investigation-CONICYT [FONDECYT regular #1170852, FONDAP-CONICYT #15130011, and PAI-CONICYT #PAI79170021].

Funding Information:
The authors would like to specially thank Andres Caicedo (Universidad San Francisco de Quito) for scientific assistance regarding the Mitoception protocol, Alex Cabrera, Hector Andrés Ramirez, and Yessia Hidalgo (C4C‐Regenero Flow Cytometry Facility) for assistance with flow cytometry and cell sorting, Macarena Ocaña and Claudia Rubí (C4C‐Regenero Animal Facility) for technical expertise and assistance in the experiments, Álvaro Elorza (Universidad Andrés Bello) for Seahorse services, and also the members of the C4C laboratory for support and helpful discussion. This work was supported by grants from National Agency for Investigation and Development: ANID (Agencia Nacional de Investigación y Desarrollo) previously branded as the Chilean National Commission for Scientific and Technological Investigation‐CONICYT [FONDECYT regular #1170852, FONDAP‐CONICYT #15130011, and PAI‐CONICYT #PAI79170021]. in vivo

Publisher Copyright:
© 2020 The Authors

Keywords

  • T regulatory cells
  • graft-versus-host disease
  • immunosuppression
  • mesenchymal stem cells
  • mitochondrial transfer

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