CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway

Yedidya Saiman, Ritu Agarwal, Da Shawn A. Hickman, Michel Fausther, Ahmed El-Shamy, Jonathan A. Dranoff, Scott L. Friedman, Meena B. Bansal

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Liver fibrosis, with subsequent development of cirrhosis and ultimately portal hypertension, results in the death of patients with end-stage liver disease if liver transplantation is not performed. Hepatic stellate cells (HSCs), central mediators of liver fibrosis, resemble tissue pericytes and regulate intrahepatic blood flow by modulating pericapillary resistance. Therefore, HSCs can contribute to portal hypertension in patients with chronic liver disease (CLD). We have previously demonstrated that activated HSCs express functional chemokine receptor, CXCR4, and that receptor engagement by its ligand, CXCL12, which is increased in patients with CLD, leads to further stellate cell activation in a CXCR4-specific manner. We therefore hypothesized that CXCL12 promotes HSC contraction in a CXCR4-dependent manner. Stimulation of HSCs on collagen gel lattices with CXCL12 led to gel contraction and myosin light chain (MLC) phosphorylation, which was blocked by addition of AMD3100, a CXCR4 small molecule inhibitor. These effects were further mediated by the Rho kinase pathway since both Rho kinase knockdown or Y-27632, a Rho kinase inhibitor, blocked CXCL12 induced phosphorylation of MLC and gel contraction. BAPTA-AM, a calcium chelator, had no effect, indicating that this pathway is calcium sensitive but not calcium dependent. In conclusion, CXCL12 promotes stellate cell contractility in a predominantly calcium-independent fashion. Our data demonstrates a novel role of CXCL12 in stellate cell contraction and the availability of small molecule inhibitors of the CXCL12/CXCR4 axis justifies further investigation into its potential as therapeutic target for portal hypertension.

Original languageEnglish
Pages (from-to)G375-G382
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume305
Issue number5
DOIs
StatePublished - 1 Sep 2013

Keywords

  • CXCR4
  • Liver fibrosis
  • Portal hypertension

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