SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models
Ryan D. Watkins, … , Gregory J. Gores, Rory L. Smoot
Ryan D. Watkins, … , Gregory J. Gores, Rory L. Smoot
Published June 28, 2022
Citation Information: JCI Insight. 2022;7(15):e159930. https://doi.org/10.1172/jci.insight.159930.
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Research Article Hepatology Therapeutics

SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models

Abstract

Disrupted liver regeneration following hepatectomy represents an “undruggable” clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as 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. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after 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 induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.

Authors

Ryan D. Watkins, EeeLN H. Buckarma, Jennifer L. Tomlinson, Chantal E. McCabe, Jennifer A. Yonkus, Nathan W. Werneburg, Rachel L. Bayer, Patrick P. Starlinger, Keith D. Robertson, Chen Wang, Gregory J. Gores, Rory L. Smoot

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Figure 1

NSC-87877 accelerates liver regeneration following murine partial hepatectomy.

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NSC-87877 accelerates liver regeneration following murine partial hepate...
(A) Mean liver/body weight ratio in mice treated with vehicle or NSC (7.5 mg/kg/dose, twice daily) 40 hours (n = 10-15), 72 hours (n = 6-11), and 120 hours (n = 3) after hepatectomy. (B) Plasma alanine aminotransferase (ALT) (U/L) 40 and 72 hours after hepatectomy (n = 5-7) in mice treated with vehicle or NSC. Dotted line represents the upper limit of normal (79 U/L). (C) Representative H&E-stained liver sections 40, 72, and 120 hours after hepatectomy in vehicle- and NSC-treated mice. Scale bar: 100 μm. (D) Proliferating cellular nuclear antigen (PCNA) immunoblot from murine whole liver lysates, 40 hours after hepatectomy, with GAPDH as a loading control. Representative of image of 2 independent experiments. (E) Representative Ki67 IHC-stained liver sections in vehicle- and NSC-treated mice from baseline, 40, 72, and 120 hours after hepatectomy (n = 3) quantified in 10 HPF (200×) per section. Scale bar: 100 μm. (F) Mean liver/body weight ratio in vehicle or NSC-treated mice following 4 weeks of treatment (n = 3). (G) Representative Ki67 IHC-stained liver sections in vehicle- and NSC-treated mice after 4 weeks of treatment. Ki67+ hepatocytes were quantified in 10 HPF (200×) (n = 3). Data are shown as mean ± SEM (*P < 0.05, **P < 0.01, ***P < 0.001). Statistical analysis was performed with 2-tailed Student t test.