SHP2 inhibitor augments murine liver regeneration via cytoprotective and proproliferative pathway enhancement identified by RNA sequencing

ABSTRACT: Disruption of the liver’s innate ability to regenerate represents an “undruggable” clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional co-activator which is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent activation of YAP mediated by tyrosine-protein phosphatase non-receptor type 11 (SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. Evaluation of these effects in mice with hepatocyte-specific Yap/Taz deletion demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of non-alcoholic steatohepatitis was associated with improved survival and decreased markers of injury post-hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induce a YAP-dependent pro-proliferative and cytoprotective enhancement of liver regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE198641 | GEO | 2022/03/17

REPOSITORIES: GEO