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J. Extracell. Vesicles, Aug 2024, 13 (8) | https://doi.org/10.1002/jev2.12497
Biopotency and surrogate assays to validate the immunomodulatory potency of extracellular vesicles derived from mesenchymal stem/stromal cells for the treatment of experimental autoimmune uveitis
Gagandeep Kaur 1*, Eun-Hye Bae 1*, Yu Zhang 1, Nicole Ciacciofera 1, Kyung Min Jung 1, Heather Barreda 1, Carol Paleti 1, Joo Youn Oh 2, Ryang Hwa Lee 1
1Department of Cell Biology and Genetics, Institute for Regenerative Medicine, Texas A&M University School of Medicine, College Station, Texas, USA.
2Department of Ophthalmology, Seoul National University College of Medicine, Seoul, South Korea.
*Gagandeep Kaur and Eun-Hye Bae contributed equally to this work.
Corresponding Author: Ryang Hwa Lee
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have been recognized as promising cytotherapeutics due to their demonstrated immunomodulatory effects in various preclinical models. The immunomodulatory capabilities of EVs stem from the proteins and genetic materials they carry from parent cells, but the cargo contents of EVs are significantly influenced by MSC tissues and donors, cellular age and culture conditions, resulting in functional variations. However, there are no surrogate assays available to validate the immunomodulatory potency of MSC-EVs before in vivo administration. In previous work, we discovered that microcarrier culture conditions enhance the immunomodulatory function of MSC-EVs, as well as the levels of immunosuppressive molecules such as TGF-β1 and let-7b in MSC-EVs. Building on these findings, we investigated whether TGF-β1 levels in MSC-EVs could serve as a surrogate biomarker for predicting their potency in vivo. Our studies revealed a strong correlation between TGF-β1 and let-7b levels in MSC-EVs, as well as their capacity to suppress IFN-γ secretion in stimulated splenocytes, establishing biopotency and surrogate assays for MSC-EVs. Subsequently, we validated MSC-EVs generated from monolayer cultures (ML-EVs) or microcarrier cultures (MC-EVs) using murine models of experimental autoimmune uveoretinitis (EAU) and additional in vitro assays reflecting the Mode of Action of MSC-EVs in vivo. Our findings demonstrated that MC-EVs carrying high levels of TGF-β1 exhibited greater efficacy than ML-EVs in halting disease progression in mice with EAU as well as inducing apoptosis and inhibiting the chemotaxis of retina-reactive T cells. Additionally, MSC-EVs suppressed the MAPK/ERK pathway in activated T cells, with treatment using TGF-β1 or let-7b showing similar effects on the MAPK/ERK pathway. Collectively, our data suggest that MSC-EVs directly inhibit the infiltration of retina-reactive T cells toward the eyes, thereby halting the disease progression in EAU mice, and their immunomodulatory potency in vivo can be predicted by their TGF-β1 levels.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-19)
- 국외 연구진
- 의약학 > 분자세포의학
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