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

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.

Enhanced potent immunosuppression of intracellular adipose tissue-derived stem cell extract by priming with three-dimensional spheroid formation

“…Interestingly, selective inhibition of COX-2 abrogates the effects of ADSC spheroid extracts and ADSC monolayer extracts on inducing T regulatory cell expansion. In comparison with a prior study that reported COX-2 is important for the suppression of T cell proliferation 38 , our results indicated that COX-2 inhibition by celecoxib was incapable of attenuating the immunosuppression efficiency of MSCs on activated T cell proliferation. Therefore, COX-2 is one of the key factors that partially mediates the immunomodulation effects of ADSC extracts.…”

Enhancing regenerative medicine: the crucial role of stem cell therapy

“…Inhibition of the M1 macrophage phenotype and promotion of the M2 phenotype was thought to contribute to tissue regeneration ( Chen et al, 2021 ). In addition, human MuSCs, a type of muscle SCs, can secrete mediators such as heme oxygenase-1 and prostaglandin E2 to inhibit T lymphocyte proliferation, induce Treg-like cell production and suppress the cytotoxic response of CD8+ T lymphocytes ( Charrier et al, 2022 ). Thus, SCs can produce various mediators to act on multiple immune cells, including macrophages and T cells, and play a pivotal role in regulating the immune microenvironment.…”

Adult tissue-specific stem cell interaction: novel technologies and research advances

“…MSCs enhance Treg immunosuppression through contact-dependent interactions that are partly mediated by MSC-expressed CD80 ( Mittal et al, 2022 ). Myogenic hMuStem cells suppress T cell activity and promote Treg production through paracrine or intercellular contacts ( Charrier et al, 2022 ). Thus, hMuStem cells are potent immunomodulators.…”