Persistent tailoring of MSC activation through genetic priming.
Persistent tailoring of MSC activation through genetic priming.
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通过基因启动持续调整 MSC 激活。
DOI：
10.1101/2024.02.01.578489
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Diehl,MichaelR
中科院分区：
文献类型：
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作者：
Beauregard,MichaelA;Bedford,GuyC;Brenner,DanielA;SanchezSolis,LeonardoD;Nishiguchi,Tomoki;Abhimanyu;Longlax,SantiagoCarrero;Mahata,Barun;Veiseh,Omid;Wenzel,PamelaL;DiNardo,AndrewR;Hilton,IsaacB;Diehl,MichaelR
间充质干/基质细胞（MSC）是一种有吸引力的细胞治疗平台，因为它们具有安全性和分泌广泛的免疫调节和再生分子的独特能力。然而，众所周知，MSC需要预处理或引发以提高其治疗功效。目前的引发方法对MSC活化提供有限的控制，产生短暂的作用，并且通常诱导可以增强免疫原性的促炎效应物的表达。在这里，我们描述了一种遗传引发方法，可以通过炎症刺激反应性转录因子干扰素反应因子1（IRF 1）的受控表达，选择性和可持续地提高MSC的效力。工程化以超表达IRF 1的MSC重现了许多核心应答，这些应答通过使用促炎细胞因子干扰素-γ（IFN-γ）的生化引发来获得。这包括抗炎效应分子的上调和MSC抑制T细胞活化的能力的增强。然而，我们发现IRF 1介导的遗传引发比生化引发更持久，并且可以规避IFN-γ依赖的免疫原性MHC II类分子的表达。总之，可持续激活和选择性定制MSC引发反应的能力创造了更全面地编程MSC激活以用于治疗应用的可能性。
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.