Human MuStem cells repress T-cell proliferation and cytotoxicity through both paracrine and contact-dependent pathways

Marine Charrier, Judith Lorant, Rafael Contreras-Lopez, Gautier Téjédor, Christophe Blanquart, Blandine Lieubeau, Cindy Schleder, Isabelle Leroux, Sophie Deshayes, Jean François Fonteneau, Candice Babarit, Antoine Hamel, Armelle Magot, Yann Péréon, Sabrina Viau, Bruno Delorme, Patricia Luz-Crawford, Guillaume Lamirault, Farida Djouad, Karl Rouger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Muscular dystrophies (MDs) are inherited diseases in which a dysregulation of the immune response exacerbates disease severity and are characterized by infiltration of various immune cell types leading to muscle inflammation, fiber necrosis and fibrosis. Immunosuppressive properties have been attributed to mesenchymal stem cells (MSCs) that regulate the phenotype and function of different immune cells. However, such properties were poorly considered until now for adult stem cells with myogenic potential and advanced as possible therapeutic candidates for MDs. In the present study, we investigated the immunoregulatory potential of human MuStem (hMuStem) cells, for which we previously demonstrated that they can survive in injured muscle and robustly counteract adverse tissue remodeling. Methods: The impact of hMuStem cells or their secretome on the proliferative and phenotypic properties of T-cells was explored by co-culture experiments with either peripheral blood mononucleated cells or CD3-sorted T-cells. A comparative study was produced with the bone marrow (BM)-MSCs. The expression profile of immune cell-related markers on hMuStem cells was determined by flow cytometry while their secretory profile was examined by ELISA assays. Finally, the paracrine and cell contact-dependent effects of hMuStem cells on the T-cell-mediated cytotoxic response were analyzed through IFN-γ expression and lysis activity. Results: Here, we show that hMuStem cells have an immunosuppressive phenotype and can inhibit the proliferation and the cytotoxic response of T-cells as well as promote the generation of regulatory T-cells through direct contact and via soluble factors. These effects are associated, in part, with the production of mediators including heme-oxygenase-1, leukemia inhibitory factor and intracellular cell adhesion molecule-1, all of which are produced at significantly higher levels by hMuStem cells than BM-MSCs. While the production of prostaglandin E2 is involved in the suppression of T-cell proliferation by both hMuStem cells and BM-MSCs, the participation of inducible nitric oxide synthase activity appears to be specific to hMuStem cell-mediated one. Conclusions: Together, our findings demonstrate that hMuStem cells are potent immunoregulatory cells. Combined with their myogenic potential, the attribution of these properties reinforces the positioning of hMuStem cells as candidate therapeutic agents for the treatment of MDs.

Original languageEnglish
Article number7
Pages (from-to)7
JournalStem Cell Research and Therapy
Volume13
Issue number1
DOIs
StatePublished - 10 Jan 2022

Bibliographical note

Funding Information:
We thank Anne Fernandez (Institut de G?n?tique Humaine, CNRS UMR 9002; Universit? de Montpellier, France) and C?dric Menard (INSERM UMR1236, Rennes, France) for helpful advice and discussions to improve the experimental design.

Funding Information:
This work was supported by a grant from the “Fonds Européen de Développement Régional” (FEDER; No. 38436 and No. PL0003686). It was performed in the context of the IHU-CESTI project that received French government financial support managed by the ANR (Agence Nationale de la Recherche) through the investment of the future program ANR-10-IBHU-005. The IHU-CESTI project was also supported by grants from the Région Pays de la Loire and Nantes Métropole. MC was recipient of a Ph.D grant from the French Ministry of Higher Education, Research and Innovation.

Publisher Copyright:
© 2021, The Author(s).

© 2021. The Author(s).

Keywords

  • Cell therapy
  • Human adult stem cell
  • Immunomodulation
  • Muscular dystrophy
  • MuStem cell
  • T-cell

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