Integration of transcriptomics and metabolomics reveals pathways involved in MDSC supernatant attenuation of TGF-β1-induced myofibroblastic differentiation of mesenchymal stem cells
Integration of transcriptomics and metabolomics reveals pathways involved in MDSC supernatant attenuation of TGF-β1-induced myofibroblastic differentiation of mesenchymal stem cells
复制标题
DOI：
10.1007/s00441-022-03681-2
复制
发表时间：
2022-09
影响因子：
3.6
通讯作者：
Y. Cheuk;Xinhao Niu;Yongxin Mao;Jiawei Li;Jiyan Wang;Shihao Xu;Yongsheng Luo;Weixi Wang;Xuanchuan Wang;Yi Zhang;R. Rong
中科院分区：
文献类型：
--
作者：
Y. Cheuk;Xinhao Niu;Yongxin Mao;Jiawei Li;Jiyan Wang;Shihao Xu;Yongsheng Luo;Weixi Wang;Xuanchuan Wang;Yi Zhang;R. Rong
过度表达转化生长因子β 1（transforming growth factor b1，TGF-β1）可诱导骨髓间充质干细胞（mesenchymal stem cells，MSCs）向肌纤维母细胞分化，而骨髓来源的抑制细胞（myeloid-derived suppressor cell，MDSC）培养上清可减弱这种分化。然而，TGF-β1的促成肌纤维细胞作用和MDSC上清液在MSC中的抗成肌纤维细胞作用尚未完全阐明。为了进一步阐明潜在的机制并确定潜在的治疗靶点，我们使用了转录组学和代谢组学相结合的综合策略。在TGF-β1和MDSC上清液处理后24 h收集骨髓MSC用于RNA测序和非靶向代谢组学分析。然后分析整合的数据以确定显著的基因-代谢物相关性。通过基因本体论（GO）功能注释和京都基因与基因组百科全书（KEGG）途径分析，对差异表达基因（DEG）和差异表达代谢物（DEM）进行分析，探讨MSCs向肌纤维母细胞分化的机制。转录组学和代谢组学数据的整合突出了TGF-β1和MDSC上清液处理后糖酵解/糖异生和嘌呤代谢的显著协调变化。通过结合转录组学和代谢组学分析，本研究表明，糖酵解/代谢产物生成和嘌呤代谢是骨髓间充质干细胞向肌纤维母细胞分化所必需的，并可能作为MDSC上清液治疗纤维化的机制研究和临床实践的有希望的靶点。
Overexposure to transforming growth factor b1 (TGF-β1) induces myofibroblastic differentiation of mesenchymal stem cells (MSCs), which could be attenuated by myeloid-derived suppressor cell (MDSC) supernatant. However, the promyofibroblastic effects of TGF-β1 and the antimyofibroblastic effects of MDSC supernatant in MSCs have not been fully elucidated. To further clarify the latent mechanism and identify underlying therapeutic targets, we used an integrative strategy combining transcriptomics and metabolomics. Bone marrow MSCs were collected 24 h following TGF-β1 and MDSC supernatant treatment for RNA sequencing and untargeted metabolomic analysis. The integrated data were then analyzed to identify significant gene-metabolite correlations. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) were assessed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for exploring the mechanisms of myofibroblastic differentiation of MSCs. The integration of transcriptomic and metabolomic data highlighted significantly coordinated changes in glycolysis/gluconeogenesis and purine metabolism following TGF-β1 and MDSC supernatant treatment. By combining transcriptomic and metabolomic analyses, this study showed that glycolysis/gluconeogenesis and purine metabolism were essential for the myofibroblastic differentiation of MSCs and may serve as promising targets for mechanistic research and clinical practice in the treatment of fibrosis by MDSC supernatant.