Beauregard, Michael A.Bedford, Guy C.Brenner, Daniel A.Sanchez Solis, Leonardo D.Nishiguchi, TomokiAbhimanyuLonglax, Santiago CarreroMahata, BarunVeiseh, OmidWenzel, Pamela L.DiNardo, Andrew R.Hilton, Isaac B.Diehl, Michael R.2024-11-202024-11-202024Beauregard, M. A., Bedford, G. C., Brenner, D. A., Sanchez Solis, L. D., Nishiguchi, T., Abhimanyu, Longlax, S. C., Mahata, B., Veiseh, O., Wenzel, P. L., DiNardo, A. R., Hilton, I. B., & Diehl, M. R. (2024). Persistent tailoring of MSC activation through genetic priming. Molecular Therapy - Methods & Clinical Development, 32(3), 101316. https://doi.org/10.1016/j.omtm.2024.101316https://hdl.handle.net/1911/118040Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress T cell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.engExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Journal articlemesenchymal stem cellsprimingimmunosuppressioninterferon gamma licensingsignaling pathway engineeringimmunomodulationSTAT1IRF11-s2-0-S2329050124001323-mainhttps://doi.org/10.1016/j.omtm.2024.101316