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Immunologic Research

, Volume 66, Issue 1, pp 207–218 | Cite as

Induction of CD4+CD25+Foxp3+ regulatory T cells by mesenchymal stem cells is associated with RUNX complex factors

  • Maryam Khosravi
  • Ali Bidmeshkipour
  • Ali Moravej
  • Suzzan Hojjat-Assari
  • Sina Naserian
  • Mohammad Hossein Karimi
Original Article
  • 295 Downloads

Abstract

Among the particular immunomodulation properties of mesenchymal stem cells (MSCs), one relies on their capacity to regulatory T cell (Treg) induction from effector T cells. Stable expression of Foxp3 has a dominant role in suppressive phenotype and stability of induced regulatory T cells (iTregs). How MSCs induce stable Foxp3 expression in iTregs remains unknown. We previously showed MSCs could enhance demethylation of Treg-specific demethylated region (TSDR) in iTregs in cell-cell contact manner (unpublished data). Here, we evaluated the possible effect of MSCs on the mRNA expression of Runx complex genes (Runx1, Runx3, and CBFB) that perch on TSDR in iTregs and play the main role in suppressive properties of Tregs, a regulatory pathway that has not yet been explored by MSCs. Also, we investigated the mRNA expression of MBD2 that promotes TSDR demethylation in Tregs. We first showed that in vitro MSC-iTreg induction was associated with strong mRNA modifications of genes involved in Runx complex. We next injected high doses of MSCs in a murine model of C57BL/6 into Balb/C allogeneic skin transplantation to prolong allograft survival. When splenocytes of grafted mice were analyzed, we realized that the Foxp3 expression was increased at day 5 and 10 post-graft merely in MSC-treated mice. Furthermore, Foxp3 mRNA expression was associated with modified Runx complex mRNA expression comparable to what was shown in in vitro studies. Hence, our data identify a possible mechanism in which MSCs convert conventional T cells to iTreg through strong modifications of mRNA of genes that are involved in Runx complex of Foxp3.

Keywords

Mesenchymal stem cells Regulatory T cells Runx complex Demethylation 

Abbreviations

MSCs

Mesenchymal stem cells

iTregs

Induced regulatory T cells

DCs

Dendritic cells

NKs

Natural killer cells

IL-12

Interleukin-12

TNFα

Tumor necrosis factor-α

nTregs

Natural Tregs

Notes

Acknowledgements

MK would like to express her deep gratitude to Professor José L. Cohen, Shiraz Organ Transplant Research Center, IFRES-INT, and INSERM U1197 team 1, for constant supporting.

Author contributions

MK built and performed the experiments, analyzed the data, and wrote the manuscript. MHK and AB contributed to building the research and revised the manuscript. AM performed the experiments and revised the manuscript. SHA analyzed the data and revised the manuscript. SN assisted with experimental revisions and wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12026_2017_8973_MOESM1_ESM.docx (1.9 mb)
ESM 1 (DOCX 1935 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Maryam Khosravi
    • 1
    • 2
    • 3
  • Ali Bidmeshkipour
    • 2
  • Ali Moravej
    • 4
  • Suzzan Hojjat-Assari
    • 3
  • Sina Naserian
    • 5
  • Mohammad Hossein Karimi
    • 1
  1. 1.Transplant Research CenterShiraz University of Medical SciencesShirazIran
  2. 2.Department of Biology, Faculty of ScienceRazi UniversityKermanshahIran
  3. 3.Institut Français de Recherche et d’Enseignement Supérieur à l’International (IFRES-INT)ParisFrance
  4. 4.Noncommunicable Diseases Research CenterFasa University of Medical SciencesFasaIran
  5. 5.Inserm, U1197, Hôpital Paul BrousseVillejuifFrance

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