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

EMBO Molecular Medicine

Chider Chen⁴  Kentaro Akiyama³  Takayoshi Yamaza²  Yong-Ouk You⁴  Xingtian Xu⁴  Bei Li¹  Yimin Zhao¹ 

[1] School of Stomatology, Fourth Military Medical University, Xi'an, Shanxi, China;Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Fukuoka, Japan;Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Kita-ku, Okayama, Japan;Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, USA

关键词: immunomodulation;    mesenchymal stem cell;    telomerase;   

DOI  :  10.1002/emmm.201303000

来源: Wiley

【 摘 要 】

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.

Synopsis

Bone marrow mesenchymal stem cells (BMMSC) have therapeutic properties in immune disorders. Telomerase function is shown to not only be critical for BMMSC stemness and osteogenic differentiation, but also to regulate BMMSC-mediated immune therapies.

• Telomerase governs immunomodulatory properties of BMMSCs.
• TERT serves as a transcription modulator to regulate FASL expression.
• Aspirin increases immunomodulation of BMMSCs through TERT activation.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.