Persistent tailoring of MSC activation through genetic priming

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dc.contributor.advisorDiehl, Michael Ren_US
dc.creatorBeauregard, Michael Andrewen_US
dc.date.accessioned2025-01-17T17:23:21Zen_US
dc.date.available2025-01-17T17:23:21Zen_US
dc.date.created2024-12en_US
dc.date.issued2024-12-03en_US
dc.date.submittedDecember 2024en_US
dc.date.updated2025-01-17T17:23:21Zen_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 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 IRF1 (interferon response factor 1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFNγ). 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 IFNγ-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.format.mimetypeapplication/pdfen_US
dc.identifier.urihttps://hdl.handle.net/1911/118233en_US
dc.language.isoenen_US
dc.subjectIRF1en_US
dc.subjectSTAT1en_US
dc.subjectimmunomodulationen_US
dc.subjectimmunosuppressionen_US
dc.subjectinterferon gamma licensingen_US
dc.subjectmesenchymal stem cellsen_US
dc.subjectprimingen_US
dc.subjectsignaling pathway engineeringen_US
dc.titlePersistent tailoring of MSC activation through genetic primingen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBioengineeringen_US
thesis.degree.disciplineBioengineeringen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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