Persistent tailoring of MSC activation through genetic priming

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dc.citation.articleNumber101316en_US
dc.citation.issueNumber3en_US
dc.citation.journalTitleMolecular Therapy - Methods & Clinical Developmenten_US
dc.citation.volumeNumber32en_US
dc.contributor.authorBeauregard, Michael A.en_US
dc.contributor.authorBedford, Guy C.en_US
dc.contributor.authorBrenner, Daniel A.en_US
dc.contributor.authorSanchez Solis, Leonardo D.en_US
dc.contributor.authorNishiguchi, Tomokien_US
dc.contributor.authorAbhimanyuen_US
dc.contributor.authorLonglax, Santiago Carreroen_US
dc.contributor.authorMahata, Barunen_US
dc.contributor.authorVeiseh, Omiden_US
dc.contributor.authorWenzel, Pamela L.en_US
dc.contributor.authorDiNardo, Andrew R.en_US
dc.contributor.authorHilton, Isaac B.en_US
dc.contributor.authorDiehl, Michael R.en_US
dc.date.accessioned2024-11-20T15:52:01Zen_US
dc.date.available2024-11-20T15:52:01Zen_US
dc.date.issued2024en_US
dc.description.abstractMesenchymal 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.en_US
dc.identifier.citationBeauregard, 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.2024.101316en_US
dc.identifier.digital1-s2-0-S2329050124001323-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.omtm.2024.101316en_US
dc.identifier.urihttps://hdl.handle.net/1911/118040en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsExcept 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subject.keywordmesenchymal stem cellsen_US
dc.subject.keywordprimingen_US
dc.subject.keywordimmunosuppressionen_US
dc.subject.keywordinterferon gamma licensingen_US
dc.subject.keywordsignaling pathway engineeringen_US
dc.subject.keywordimmunomodulationen_US
dc.subject.keywordSTAT1en_US
dc.subject.keywordIRF1en_US
dc.titlePersistent tailoring of MSC activation through genetic primingen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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