Myocardin‐related transcription factor A drives ROS‐fueled expansion of hepatic stellate cells by regulating p38‐MAPK signalling

作者：Wenhui Dong, Ming Kong, Hong Liu, Yujia Xue, Zilong Li, Yutong Wang, Yong Xu · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.688 · 被引用次数：24 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Liver Diseases and Immunity

We describe in this letter a novel retrograde signalling mechanism that highlights a myofibroblast-specific role for myocardin-related transcription factor A (MRTF-A), also known as MKL1, in liver fibrosis. Liver fibrosis is considered a common pathological process in virtually all end-stage liver diseases. Absent from the liver under physiological conditions, myofibroblasts quickly emerge and expand as a result of liver injuries to mediate the pro-fibrogenic response. Hepatic stellate cells (HSCs), tucked between the liver parenchyma and the hepatic sinusoid, is considered as the predominant source from which myofibroblasts are derived regardless of aetiology.1 Reactive oxygen species (ROS) fuels HSC proliferation via a network of signalling cascades. Mitogen-activated protein kinases (MAPKs) are well-documented for their regulatory roles in ROS-driven HSC proliferation and liver fibrosis by programming transcriptional events in the nucleus. How the cytoplasm-nucleus crosstalk influences MAPK signalling and contributes to ROS-dependent HSC proliferation is not well understood. MRTF-A is a transcriptional modulator implicated in the pathogenesis of a wide range of human diseases. Despite the near-unanimous view that MRTF-A is a pivotal regulator of myofibroblast trans-differentiation,2 there is no direct genetic evidence to support or refute the hypothesis that myofibroblast-specific MRTF-A deletion is sufficient to suppress liver fibrosis in vivo due to its universal express...