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bioRxiv · 10.1101/2025.04.19.649667

Alpha-1 Antitrypsin Overexpressing Mesenchymal Stem/Stromal Cells Reverses Type 1 Diabetes via Promoting Treg Function and CD8+ T cell exhaustion

Wang, H.·Wei, H.·Gou, W.·Kim, J.·Subramanian, S.·Yeung, T.·Chakraborty, P.·Mehrotra, S.·Berto, S.·Strange, C.
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Abstract

Mesenchymal stem/stromal cell (MSC) therapy holds great promise as both a therapeutic option and as a biofactory, as cells produce therapeutic proteins to augment their efficacy in disease treatment. This study investigates the therapeutic effects and the mechanistic insights of alpha-1 antitrypsin overexpressing MSCs (AAT-MSCs) in diabetes prevention and treatment. A single infusion of AAT-MSCs not only delayed diabetes onset but reversed new-onset type 1 diabetes (T1D) in the nonobese diabetic (NOD) mice. Using single-cell RNA sequencing, flow cytometry, and functional analyses, we characterized the impact of AAT-MSCs on immune cells, particularly CD4+ and CD8+ T cells, in pancreatic lymph nodes (PLNs) and islets of NOD mice. AAT-MSCs enhanced the immunosuppressive function and the communication of regulatory T cells (Tregs) with other immune cells while reducing the numbers of T helper 1 (Th1) cells and CD8+ cytotoxic T cells. In vitro experiments further confirmed the capacity of AAT-MSCs to promote the proliferation of Tregs, which consequently fostered an exhausted phenotype in CD8+ T cells, thereby facilitating {beta} cell survival and potentially aiding in diabetes remission. Thus, our findings underscore the significant protective effects of AAT-MSCs, delineate their novel mechanistic insight on recipient immune cells, and provide evidence for the clinical application of AAT-MSCs in treating T1D.

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Wang, H., Wei, H., Gou, W., Kim, J., Subramanian, S., Yeung, T., Chakraborty, P., Mehrotra, S., Berto, S., Strange, C.. 2025-04-21. Alpha-1 Antitrypsin Overexpressing Mesenchymal Stem/Stromal Cells Reverses Type 1 Diabetes via Promoting Treg Function and CD8+ T cell exhaustion. https://doi.org/10.1101/2025.04.19.649667

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