Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles

Abstract

Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC‐derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1‐immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1‐expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF‐conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A‐containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. Conclusion: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA‐laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. (Hepatology 2015;61:1041–1055)

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

“…In other studies, exosomes were capable of transducing Hedgehog signals (13). Microparticles have also been implicated in cirrhosis and portal hypertension, with evidence that such particles may contain the angiogenic molecule VEGF and other studies providing evidence that these particles can mediate hemodynamic disturbances associated with cirrhosis (50). Our study adds to these existing models not only by showing a role for exosomes in paracrine signaling relevant to cir-FIGURE 6.…”

Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury

“…3E). Additionally, the PF markers NTPDase2 ( Entpd2 ) and type XV collagen26 ( Col15a1 ) were significantly enriched in Thy1 MCs (Supporting Fig. S3A).…”

“…In our analysis, periportal Thy1‐expressing cells stably expressed α‐SMA even at normal states, along with many other PF markers, such as elastin and NTPDase2. However, cells that line the vascular wall of the portal vein also express most, if not all, of the known PF markers18, 26 (Supporting Figs. S1B, S6B) and are the mesenchymal‐type cell population, thereby falling into the category of conventional PFs.…”

Closed-Loop Lumped Parameter Modeling of Hemodynamics During Cirrhogenesis in Rats

“…Cirrhosis may induce a decrease of the MAP, mainly due to vasodilation of the splanchnic and peripheral vascular beds. Niederberger et al reported a halving of the systemic vascular resistance after 9-10 weeks of CCL 4 -intoxication in rats [24]. At that time, rats had already developed cirrhotic ascites.…”

“…Eventually, normal liver tissue is replaced by diffuse fibrosis, vascularized ƒfibrotic septa, and regenerative nodules [2]. Previous studies have shown that the associated morphological reorganization of the hepatic architecture contributes to the increasing intrahepatic vascular resistance (IHVR), dysregulating liver perfusion [3,4].…”