BACKGROUND Mesenchymal stromal cells (MSCs), due to their regenerative and immunomodulatory properties, are therapeutically used for diseases, including heart failure. As early gestational-phase embryonic tissues exhibit extraordinary regenerative potential, fetal MSCs exposed to inflammation offer a unique opportunity to evaluate molecular mechanisms underlying preferential healing, and investigate their inherent abilities to communicate with the immune system during development. The principal aim of this study was to evaluate the effects of interferon-γ (IFNγ) on the immunomodulatory effects of first-trimester human fetal cardiac (hfc)-MSCs. METHODS hfcMSCs (gestational week 8) were exposed to IFNγ, with subsequent analysis of the whole transcriptome, based on RNA sequencing. Exploration of surface-expressed immunoregulatory mediators and modulation of T cell responses were performed by flow cytometry. Presence and activity of soluble mediators were assessed by ELISA or high-performance liquid chromatography. RESULTS Stimulation of hfcMSCs with IFNγ revealed significant transcriptional changes, particularly in respect to the expression of genes belonging to antigen presentation pathways, cell cycle control, and interferon signaling. Expression of immunomodulatory genes and associated functional changes, including indoleamine 2,3-dioxygenase activity, and regulation of T cell activation and proliferation via programmed cell death protein (PD)-1 and its ligands PD-L1 and PD-L2, were significantly upregulated. These immunoregulatory molecules diminished rapidly upon withdrawal of inflammatory stimulus, indicating a high degree of plasticity by hfcMSCs. CONCLUSIONS To our knowledge, this is the first study performing a systematic evaluation of inflammatory responses and immunoregulatory properties of first-trimester cardiac tissue. In summary, our study demonstrates the dynamic responsiveness of hfcMSCs to inflammatory stimuli. Further understanding as to the immunoregulatory properties of hfcMSCs may be of benefit in the development of novel stromal cell therapeutics for cardiovascular disease.

中文翻译：

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干扰素-γ对人胎儿心脏间充质基质细胞的免疫调节作用。

背景技术间充质基质细胞（MSC）由于其再生和免疫调节特性，被治疗性用于疾病，包括心力衰竭。由于早期妊娠阶段的胚胎组织显示出非凡的再生潜能，暴露于炎症的胎儿MSC提供了独特的机会来评估优先治疗的分子机制，并研究它们在发育过程中与免疫系统进行沟通的固有能力。这项研究的主要目的是评估干扰素-γ（IFNγ）对早孕期人胎儿心脏（hfc）-MSCs免疫调节作用的影响。方法将hfcMSCs（妊娠第8周）暴露于IFNγ，然后根据RNA测序对整个转录组进行分析。通过流式细胞仪探索表面表达的免疫调节介质和调节T细胞反应。可溶性介体的存在和活性通过ELISA或高效液相色谱法进行评估。结果用IFNγ刺激hfcMSCs显示出显着的转录变化，特别是在属于抗原呈递途径的基因表达，细胞周期控制和干扰素信号传导方面。免疫调节基因的表达和相关功能变化，包括吲哚胺2,3-二加氧酶活性，以及​​通过程序性细胞死亡蛋白（PD）-1及其配体PD-L1和PD-L2对T细胞活化和增殖的调节，均显着上调。撤消炎症刺激后，这些免疫调节分子迅速消失，表明hfcMSC具有高度可塑性。结论据我们所知，这是第一个对孕早期心脏组织的炎症反应和免疫调节特性进行系统评价的研究。总之，我们的研究证明了hfcMSC对炎症刺激的动态反应。对hfcMSCs的免疫调节特性的进一步了解可能有益于心血管疾病新型基质细胞治疗剂的开发。