Lu Zixuan, Zhou Yuming, Li Chengyu, Abd El-Aty A M, Liu Chengxia, Luan Xiying, Wang Bin, Wang Guoyan
Department of Immunology, Binzhou Medical University, Yantai, China.
Medical Laboratory of the Second School of Clinical Medicine, Binzhou Medical University, Yantai, China.
Front Immunol. 2025 May 15;16:1570916. doi: 10.3389/fimmu.2025.1570916. eCollection 2025.
The molecular characteristics of acute graft--host disease (aGVHD) in different lung lobes and the treatment of aGVHD with mesenchymal stem cells are still poorly understood. In addition, despite the important role of acetylation on lysine 27 of histone H3 (H3K27ac) in the inflammatory response, little is known about genome-wide H3K27ac in GVHD and MSC treatment. In this study, we described 55 paired transcriptomes and genome-wide H3K27ac in five lung lobes, with groups designated as follows: control, GVHD, human placenta-derived MSC (hPMSC)-treated, and PBS-treated groups. We observed that inflammatory pathways were upregulated in GVHD but downregulated in hPMSCs. One algorithm was designed to identify the genes implicated in the prevention of GVHD by hPMSCs (the Rein02 gene), shedding light on a gene set with 892 Rein02 genes that are shared by all lobes and enriched in inflammatory pathways such as TNF-α signaling via NF-κb. The genome-wide H3K27ac data revealed lobe-specific patterns in the lobe behind the heart (H) and the left lobe (L) in the control and hPMSC groups, whereas these patterns were confused in the GVHD and PBS groups. Gene set enrichment analysis revealed that the hPMSC-induced variations in genome-wide H3K27ac were concentrated in the L and R3 lobes. The genes showing accordant tendencies (a-DEGs) between the transcriptome and H3K27ac highly overlapped between the a-DEGs and the Rein02 genes when hPMSCs were compared with GVHD. Integrated multiomics analysis suggested that the a-DEGs were predominantly expressed on myeloid (Fam174a, Ifi204, Slc7a11, Chil3, Capza2, Clec5a, and Clec4a2), T and NK cells (Eif3f, Cited2, Crybg1, Ndufs4, and Emb), B cells (Fam174a, Eif3f, and Blnk), and epithelial cells (Alcam, Chmp2b, and Metap2). The subset with high expression levels of these genes tended to present anti-inflammatory effects and reduced cytotoxic activity. Our study may provide new insights into the development of potential therapeutic drugs that target H3K27ac to assist in MSC treatment.
不同肺叶中急性移植物抗宿主病（aGVHD）的分子特征以及间充质干细胞治疗aGVHD的情况仍知之甚少。此外，尽管组蛋白H3赖氨酸27位点的乙酰化（H3K27ac）在炎症反应中起重要作用，但关于GVHD和间充质干细胞治疗中全基因组范围的H3K27ac情况却知之甚少。在本研究中，我们描述了五个肺叶中的55对转录组和全基因组范围的H3K27ac，分组如下：对照组、GVHD组、人胎盘来源间充质干细胞（hPMSC）治疗组和PBS治疗组。我们观察到炎症通路在GVHD中上调，但在hPMSC中下调。设计了一种算法来鉴定hPMSC预防GVHD所涉及的基因（Rein02基因），从而揭示了一个由892个Rein02基因组成的基因集，这些基因在所有肺叶中都有共享，并且在诸如通过NF-κb的TNF-α信号传导等炎症通路中富集。全基因组范围的H3K27ac数据显示，在对照组和hPMSC组中，心脏后方肺叶（H）和左肺叶（L）存在叶特异性模式，而在GVHD组和PBS组中这些模式则混淆不清。基因集富集分析表明，hPMSC诱导的全基因组范围H3K27ac变化集中在L和R3肺叶。当将hPMSC与GVHD进行比较时，转录组和H3K27ac之间显示出一致趋势的基因（a-DEGs）在a-DEGs和Rein02基因之间高度重叠。综合多组学分析表明，a-DEGs主要在髓系细胞（Fam174a、Ifi204、Slc7a11、Chil3、Capza2、Clec5a和Clec4a2）、T细胞和NK细胞（Eif3f、Cited2、Crybg1、Ndufs4和Emb）、B细胞（Fam174a、Eif3f和Blnk）以及上皮细胞（Alcam、Chmp2b和Metap2）中表达。这些基因高表达的亚群往往呈现抗炎作用并降低细胞毒性活性。我们的研究可能为开发以H3K27ac为靶点辅助间充质干细胞治疗的潜在治疗药物提供新的见解。
