Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease.
Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease.
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组织稳态需要对损伤的有效的、有限的伤口愈合反应。在慢性疾病中，不能再生实质组织导致用纤维化基质替代损失的细胞质量。决定细胞再生和纤维化的平衡的机制还没有很好地理解。在这里，我们报告说，肝纤维化肝星状细胞（HSC）在肝脏的肝细胞再生的负调节。这种负调节功能需要5-羟色胺2B受体（5-HT 2B）被5-羟色胺刺激，其通过丝裂原活化蛋白激酶1（ERK）和转录因子JunD的信号传导激活转化生长因子β1（TGF-β1）的表达，转化生长因子β 1是肝细胞增殖的有力抑制剂。选择性拮抗5-HT 2B增强急性和慢性肝损伤模型中的肝细胞生长。我们还在缺乏5-HT 2B或JunD的小鼠中或在野生型小鼠中选择性消耗HSC后观察到类似的效果。5-HT 2B的拮抗作用减弱了纤维化发生并改善了其中纤维化预先建立并进行的疾病模型中的肝功能。5-HT 2B的药理学靶向在人类中是临床安全的，并且可以治疗慢性肝病。
Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT2B is clinically safe in humans and may be therapeutic in chronic liver disease.