A New Liver-Regeneration Molecular Mechanism Involving Hepatic Stellate Cells, Kupffer Cells, and Glucose-Regulated Protein 78 as a New Hepatotrophic Factor

ABSTRACT: Background and aims: Lethal liver failure is an important clinical issue. To overcome liver failure, we focused on liver regeneration mechanisms by activation of HSCs and KCs. It is known that the HSC-secreted Mac-2 binding protein glycan isomer (M2BPGi) has a function to activate Kupffer cells (KCs) in fibrotic liver. However, the importance and functional mechanism of liver regeneration by HSCs/M2BPGi/KCs axis in remnant liver after hepatectomy are still unknown. The aim of this study is to clarify whether the HSCs-derived M2BPGi can activate KCs in damaged-liver by not only fibrosis but also after hepatectomy and to elucidate the new molecular mechanism of liver regeneration by HSCs and KCs. Methods: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs by proteomics approach. Further, the effect of Glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins on liver regeneration was examined in in vitro analysis and mouse hepatectomy model. Results: Although M2BPGi had no hepatocyte promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KCs-drived GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration in 70% hepatectomy mice and increased the survival rate in lethal 90% hepatectomy mice with liver failure. Conclusion: The M2BPGi activated-KCs extract the GRP78 which facilitates liver regeneration via activation of the proliferation potency of hepatocytes. Moreover, GRP78 administration could improve the survival in the lethal mice model. Our data suggested that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure in the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179005 | GEO | 2021/06/29

REPOSITORIES: GEO