Interaction of hepatic stellate cells with neutrophils and macrophages in the liver following oncogenic kras activation in transgenic zebrafish

Activation of hepatic stellate cells (HSC) plays a crucial role in the liver disease progression from liver fibrosis/cirrhosis to cancer. Here, we found a rapid change of microenvironment after krasV12-induction in zebrafish liver with progressively increased stromal cell number and enlarged liver size. Neutrophils and macrophages exhibited a faster response than HSCs. By manipulating the numbers of neutrophils and macrophages through morpholino knockdown, we found that macrophages contributed to both HSC survival and activation while neutrophils appear to be only required for HSC activation. Serotonin, which is essential for HSC survival and activation, was found up-regulated in hepatocytes and macrophages, but not in neutrophils after krasV12 induction. Serotonin receptor was highly expressed in HSCs; increase of the receptor activity by an agonist stimulated HSCs and oncogenic growth of the liver while an opposite effect was observed with an antagonist. Activated HSCs promoted the pro-tumorigenesis functions of neutrophils and macrophages through secretion of Tgfb1. Overall, these observations elucidated a cellular interaction in microenvironment where that upregulated serotonin in hepatocytes and macrophages activated HSCs. Since the microenvironment crosstalk plays a vital role in manipulation of liver carcinogenesis, the underlying mechanism may provide potential therapeutic targets for liver diseases.