Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression

Chider Chen, Kentaro Akiyama, Takayoshi Yamaza, Yong Ouk You, Xingtian Xu, Bei Li, Yimin Zhao, Songtao Shi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT-/- BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with β-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies.

Original languageEnglish
Pages (from-to)322-334
Number of pages13
JournalEMBO Molecular Medicine
Volume6
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Telomerase
Mesenchymal Stromal Cells
Bone Marrow
Ligands
Aspirin
Up-Regulation
Catenins
Systemic Scleroderma
Immunotherapy
Transfection
Therapeutics
T-Lymphocytes
Phenotype

Keywords

  • Immunomodulation
  • Mesenchymal stem cell
  • Telomerase

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression. / Chen, Chider; Akiyama, Kentaro; Yamaza, Takayoshi; You, Yong Ouk; Xu, Xingtian; Li, Bei; Zhao, Yimin; Shi, Songtao.

In: EMBO Molecular Medicine, Vol. 6, No. 3, 2014, p. 322-334.

Research output: Contribution to journalArticle

Chen, Chider ; Akiyama, Kentaro ; Yamaza, Takayoshi ; You, Yong Ouk ; Xu, Xingtian ; Li, Bei ; Zhao, Yimin ; Shi, Songtao. / Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression. In: EMBO Molecular Medicine. 2014 ; Vol. 6, No. 3. pp. 322-334.
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