Activated hepatic stellate cells: negative regulators of hepatocyte proliferation in liver diseases

Abstract

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-HT_2B) 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-HT_2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT_2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT_2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT_2B is clinically safe in humans and may be therapeutic in chronic liver disease.

Fig 1. Serotonin (5-HT) binds to its receptor 5-HT_2B expressed in activated hepatic stellate cells (HSCs), produces transforming growth factor β1 (TGF-β1) in diseased livers and suppresses hepatocyte proliferation

In diseased livers, activated HSCs express a subclass of the 5-HT receptors, 5-HT_2B. Serotonin binds to this receptor and activates ERK1 and 2, leading to an activation of transcription factor JunD to upregulate TGF-β1 expression. Since TGF-β1 is a powerful suppressor of hepatocyte proliferation, liver regeneration is inhibited by this mechanism. In contrast, in healthy livers, 5-HT promotes hepatocyte proliferation by directly binding to another subclass of the 5-HT receptors, 5-HT_2A. Thus, 5-HT differentially regulates hepatocyte proliferation through its different receptors.