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

ABSTRACT: 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 beta platelet-derived growth factor (?-PDGFR), which drives cellular fibrogenesis and proliferation; in contrast, normal liver has minimal ?-PDGFR expression. While the role of ?-PDGFR is well established in liver injury, its expression and contribution during liver regeneration are unknown. The aim of this study was to determine whether ?-PDGFR is induced during liver regeneration following partial hepatectomy (pHx), and to define its contribution to the regenerative response.Control mice or animals with HSC-specific ?-PDGFR-depletion underwent two-thirds pHx followed by assessment of hepatocyte proliferation and expression of ?-PDGFR. RNA-sequencing from whole liver tissue of both groups after pHx was used to uncover pathways regulated by ?-PDGFR signalling in HSCs.Beta platelet-derived growth factor expression on HSCs was up-regulated within 24 h following pHx in control mice, whereas absence of ?-PDGFR blunted the expansion of HSCs. Mice lacking ?-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 ?-PDGFR-deficient mice. This was associated with dysregulated growth in the ?-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.Beta platelet-derived growth factor 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.

SUBMITTER: Kocabayoglu P 

PROVIDER: S-EPMC4749477 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature