Comprehensive Molecular Profiles of Functionally Effective MSC-Derived Extracellular Vesicles in Immunomodulation

Hyemee Kim, Min Joung Lee, Eun Hye Bae, Jin Suk Ryu, Gagandeep Kaur, Hyeon Ji Kim, Jun Yeob Kim, Heather Barreda, Sung Youn Jung, Jong Min Choi, Taeko Shigemoto-Kuroda, Joo Youn Oh, Ryang Hwa Lee

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2 Scopus citations

Abstract

Accumulating evidence indicates that mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) exhibit immunomodulatory effects by delivering therapeutic RNAs and proteins; however, the molecular mechanism underlying the EV-mediated immunomodulation is not fully understood. In this study, we found that EVs from early-passage MSCs had better immunomodulatory potency than did EVs from late-passage MSCs in T cell receptor (TCR)- or Toll-like receptor 4 (TLR4)-stimulated splenocytes and in mice with ocular Sjögren's syndrome. Moreover, MSC-EVs were more effective when produced from 3D culture of the cells than from the conventional 2D culture. Comparative molecular profiling using proteomics and microRNA sequencing revealed the enriched factors in MSC-EVs that were functionally effective in immunomodulation. Among them, manipulation of transforming growth factor β1 (TGF-β1), pentraxin 3 (PTX3), let-7b-5p, or miR-21-5p levels in MSCs significantly affected the immunosuppressive effects of their EVs. Furthermore, there was a strong correlation between the expression levels of TGF-β1, PTX3, let-7b-5p, or miR-21-5p in MSC-EVs and their suppressive function. Therefore, our comparative strategy identified TGF-β1, PTX3, let-7b-5p, or miR-21-5p as key molecules mediating the therapeutic effects of MSC-EVs in autoimmune disease. These findings would help understand the molecular mechanism underlying EV-mediated immunomodulation and provide functional biomarkers of EVs for the development of robust EV-based therapies.

Original languageEnglish
Pages (from-to)1628-1644
Number of pages17
JournalMolecular Therapy
Volume28
Issue number7
DOIs
StatePublished - 8 Jul 2020

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    Kim, H., Lee, M. J., Bae, E. H., Ryu, J. S., Kaur, G., Kim, H. J., Kim, J. Y., Barreda, H., Jung, S. Y., Choi, J. M., Shigemoto-Kuroda, T., Oh, J. Y., & Lee, R. H. (2020). Comprehensive Molecular Profiles of Functionally Effective MSC-Derived Extracellular Vesicles in Immunomodulation. Molecular Therapy, 28(7), 1628-1644. https://doi.org/10.1016/j.ymthe.2020.04.020