Persistent Tailoring of MSC Activation Through Genetic Priming

Authors

Michael A Beauregard
Guy C Bedford
Daniel A Brenner
Leonardo D Sanchez Solis
Tomoki Nishiguchi
Abhimanyu
Santiago Carrero Longlax
Barun Mahata
Omid Veiseh
Pamela L Wenzel
Andrew R DiNardo
Isaac B Hilton
Michael R Diehl

Publication Date

9-12-2024

Journal

Molecular Therapy Methods & Clinical Development

Abstract

Mesenchymal 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.

Keywords

mesenchymal stem cells, priming, immunosuppression, interferon gamma licensing, signaling pathway engineering, immunomodulation, STAT1, IRF1

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Associated Data

PMID: 39282077