由YAP诱导的糖解驱动纤维炎症并破坏纤维细胞忠诚度
Chang-Ru Tsai1, Lin Liu2, Yi Zhao2
1Department of Integrative Physiology (C.-R.T., J.S., F.G., M.A.H.S., J.F.M.), Baylor College of Medicine, Houston, TX.
Circulation research
|October 30, 2025
概括
右心房纤维细胞表现出更高的糖解和YAP活性,驱动纤维化. 通过影响巨细胞和IGF1信号传递,YAP激活促进骨质突变细胞和纤维化.
科学领域:
- 心血管生物学 心血管生物学
- 细胞的新陈代谢
- 纤维化研究 纤维化研究
背景情况:
- 哺乳动物心室具有专门的结构和功能,但对于室内特异性转录组和代谢差异背后的机制知之甚少.
- 希波/Yes相关蛋白 (YAP) 途径调节细胞过程,希波激酶抑制心脏纤维细胞 (CF) 中的YAP,以限制纤维化和炎症.
- 雅培在调节平衡和纤维炎症期间代谢微环境中的确切作用尚不清楚.
研究的目的:
- 为了研究YAP和四个心脏腔中的糖解的活性.
- 了解YAP在心脏纤维细胞 (CF) 中的作用及其对代谢微环境的影响.
- 阐明驱动心脏内特定腔室的转录组和代谢差异的机制.
主要方法:
- 在人类单核RNA测序数据中,YAP目标和糖解基因的得分表达.
- 测量同位素标记的葡萄糖摄取在隔离的小鼠心房中,以比较左心房和右心房之间的葡萄糖摄取.
- 在小鼠CF中失活的Hippo激酶 (Lats1/Lats2) 进行代谢研究,snRNA-seq,单核测定转化酶可访问的染色质与测序,以及空间转录组学.
主要成果:
- 缺少Hippo的CFs激活了葡萄糖分解,促进了纤维炎症,抑制了葡萄糖分解抑制了纤维化.
- 升高的YAP活动破坏了纤维细胞谱系的忠实性,诱导了骨质突合产生细胞状态.
- 巨细胞分泌胰岛素样生长因子1 (IGF1) 激活IGF1信号在Hippo缺乏的CFs,增加增殖和纤维化.
结论:
- 右心房CF表现出更高的糖解和YAP活性,YAP激活驱动纤维化并诱导骨质突变细胞的细胞状态.
- YAP通过CSF1分泌促进巨细胞扩张,巨细胞通过IGF1相互信号,以增强CF扩散和纤维化.
- 在Hippo-deficient CFs中高调的IGF1受体介导着增强的增殖和纤维化,以应对巨细胞分泌的IGF1.
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