Extracellular Matrix Regulates Hepatic Stellate Cell Activation and Fibrosis

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

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Abstract

Project Summary Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection, alcohol- associated liver disease, and metabolic dysfunction-associated steatotic liver disease. Cirrhosis, the end stage of liver fibrosis, is the 11th leading cause of death in the US. To develop effective anti-fibrotics for liver fibrosis, we need a better understanding of the molecular basis of liver fibrosis. Prior to our study, hyaluronic acid (HA) was only known as a non-invasive biomarker for liver fibrosis. In the previous funding period, we determined that HA is actively synthesized by upregulated HA synthase 2 (HAS2) in activated hepatic stellate cells (HSCs) in liver fibrosis. HA synthesized by HAS2 is then converted to lower molecular weight (LMW)-HA, which activates CD44, TLR4, and Notch1 signaling, thereby activating HSCs for liver fibrosis progression. Although LMW-HA is critical for the development of fibrosis, the mechanisms of LMW-HA formation during liver fibrosis and HA-mediated fibrosis are still poorly understood. In the renewal application, we will characterize these mechanisms. The central hypothesis of this renewal application is that TMEM2, a newly identified hyaluronidase, mediates the production of extracellular LMW-HA that promotes liver fibrosis via fibrotic phenotypic changes in HSCs and liver sinusoidal endothelial cells (LSECs). Using cell-specific TMEM2 deletion mice, Aim 1 will determine the mechanism of extracellular HA catabolism by TMEM2. Aim 2 will determine the regulation of TMEM2 expression by focusing on two transcription factors, HIF1α and SOX4, in hypoxic and fibrotic environments. Because both HSCs and LSECs highly express CD44, a HA receptor, Aim 3 will determine the downstream effector pathways activated by HA and TMEM2 in HSCs and LSECs for liver fibrosis development. Aim 3 will also investigate whether the crosstalk between LSECs and HSCs is crucial for the HA-TMEM2-CD44-mediated HSC activation and fibrosis progression. We anticipate our results will provide valuable insights into the poorly understood mechanism of regulation of the profibrogenic activity of HA and its effect on HSCs and LSECs in the development of liver fibrosis. This will improve our understanding of the clinical value of HA, not only as a biomarker for liver fibrosis but also as a cause of liver fibrosis and a target for effective treatments.