Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

Abstract

Background/Aims-Factors released during liver injury, such as platelet derived growth factor-BB (PDGF) promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The Hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth.

Hepatic Stellate Cell-derived Delta-like Homolog 1 (DLK1) Protein in Liver Regeneration

“…Shh shown to be involved in activation of HSCs (6,8,42). In day 7 culture-activated HSCs, Dlk1 mRNA expression is suppressed by inhibition of canonical Wnt signaling with the Wnt co-receptor antagonist Dickkopf-1 (DKK1), necdin shRNA, and the Shh inhibitor cyclopamine (Fig.…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…In vitro , it has been well documented that recombinant Shh protein induces an activated phenotype of cultured lung fibroblasts and hepatic stellate cells, as manifested by an augmented cell proliferation, migration, excessive ECM production (Hu et al, 2015; Yang et al, 2008). Shh signaling is upregulated in animal models and patients with idiopathic pulmonary fibrosis (IPF), other interstitial lung diseases and nonalcoholic fatty liver disease (NAFLD), with nuclear accumulation of Gli1, Gli2 in the fibrotic areas and an increased expression of the Shh downstream target genes.…”

Sonic hedgehog mediates a novel pathway of PDGF-BB–dependent vessel maturation

“…27 Recent data demonstrated that Shh contributes to PDGF-BBstimulated fibroblast migration. 20 Because PDGF-BB is one of the main chemotactic factors for SMCs, we hypothesized that Hh proteins could work in combination with PDGF-BB to promote SMC migration. As shown in Figure 1A, Hh blocking antibody 5E1 decreased PDGF-BB-induced migration of commercial rat aortic primarycultured SMCs.…”

“…Because Shh was previously shown to promote SMC proliferation in vitro [16][17][18] and to drive the proliferative effect of PDGF-BB, 20 we checked the role of the Hh pathway in NG2…”

“…At the cellular level, recombinant Shh was shown to induce SMC and pericyte proliferation and survival [16][17][18][19] and to contribute to PDGF-BB-induced myofibroblast proliferation. 20 Even though Shh was shown to induce the migration of various cell types such as fibroblasts, 21 ECs, 22 endothelial progenitors, 23 and monocytes, 24 its role and mechanism in SMC migration in vitro and in MC recruitment in vivo have never been investigated.…”