These authors contributed equally to this study.
Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression
Article first published online: 13 JAN 2014
© 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 3, pages 322–334, March 2014
How to Cite
EMBO Mol Med (2014) 6, 322–334
- Issue published online: 7 MAR 2014
- Article first published online: 13 JAN 2014
- Manuscript Accepted: 12 NOV 2013
- Manuscript Revised: 10 NOV 2013
- Manuscript Received: 4 MAY 2013
- National Institute of Dental and Craniofacial Research
- National Institutes of Health
- Department of Health and Human Services. Grant Numbers: R01DE017449, R01DE019413
- California Institute for Regenerative Medicine. Grant Number: RN1-00572
- National Natural Science Foundation of China. Grant Number: 81020108019
- National Basic Research Program (973 Program) of China. Grant Number: 2011CB964700
- mesenchymal stem cell;
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.
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.