Induction and contribution of beta platelet‐derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice

Abstract

Background Hepatic stellate cells (HSCs) activate during injury to orchestrate the liver’s inflammatory and fibrogenic responses. A critical feature of HSC activation is the rapid induction of β-PDGFR, which drives cellular fibrogenesis and proliferation; in contrast, normal liver has minimal β-PDGFR expression. While the role of β-PDGFR is well established in liver injury, its expression and contribution during liver regeneration are unknown. The aim of this study is to determine whether β-PDGFR is induced during liver regeneration following partial hepatectomy (pHx), and to define its contribution to the regenerative response. Methods Control mice or animals with HSC-specific β-PDGFR-depletion underwent two-thirds pHx followed by assessment of hepatocyte proliferation and expression of β-PDGFR. RNA-sequencing from whole liver tissue of both groups after pHx was used to uncover pathways regulated by β-PDGFR signaling in HSCs. Results β-PDGFR expression on HSCs was upregulated within 24 hours (h) following pHx in control mice, whereas absence of β-PDGFR blunted the expansion of HSCs. Mice lacking β-PDGFR displayed prolonged increases of transaminase levels within 72 h following pHx. Hepatocyte proliferation was impaired within the first 24 h based on Ki-67 and PCNA expression in β-PDGFR-deficient mice. This was associated with dysregulated growth in the β-PDGFR-deficient mice based on RNAseq with pathway analysis, and real time quantitative PCR, which demonstrated reduced expression of Hgf, Igfbp1, Mapk and Il-6. Conclusions β-PDGFR is induced in HSCs following surgical pHx and its deletion in HSCs leads to prolonged liver injury. However, there is no significant difference in liver regeneration.

IL‐6 Trans‐signaling Controls Liver Regeneration After Partial Hepatectomy

“…Hepatic stellate cells (HSCs) are a known source of HGF following PHX . To answer the question of whether IL‐6 classic and/or trans‐signaling trigger expression of HGF, rat HSCs were analyzed.…”

“…Hepatic stellate cells (HSCs) are a known source of HGF following PHX. (31) To answer the question of whether IL-6 classic and/or trans-signaling trigger expression of HGF, rat HSCs were analyzed. Interestingly, HSCs express IL-6R and Gp130 on the mRNA level as determined by quantitative real-time PCR (Fig.…”

Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12

“…However, HSCs not only play a role in fibrosis 31 but also, as suggested by our data, modulate steatohepatitis. 32 Recently, it has been suggested that HSCs produce cytokines and chemokines that act as antigen-presenting cells. 33 It has also been shown that activated HSCs secrete IL-6 and TNFa, which further suppress the expression of HNF1a and SHP-1 in hepatocytes and lead to more inflammation and fibrogenesis.…”

Update on the Mechanisms of Liver Regeneration

“…When PDGFRβ knockout mice were subjected to PHx, hepatic injury markers serum alanine aminotransferase and aspartate aminotransferase were significantly elevated. 49 There was also a concomitant reduction in the number of HSCs at 72 hours compared with controls. There was a marked reduction in PCNA and K i -67 staining in the hepatocytes during LR, in addition to decreases in growth factors HGF, IGF1, and IGFPB1.…”