SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models
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
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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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 5

NSC improves postoperative mortality in murine NASH model.

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NSC improves postoperative mortality in murine NASH model. (A) NASH indu...
(A) NASH induction with a high-fat, -cholesterol, -glucose/sucrose diet (FFC). (B) Mean chow control mouse liver/body weight ratio 40 and 72 hours after hepatectomy (n = 3). (C) Representative BrdU immunofluorescence staining in liver sections 40 hours after hepatectomy in vehicle- and NSC-treated chow control mice (n = 3). Scale bar: 100 μm. DAPI-counterstained cells overlayed with BrdU with quantified BrdU+ hepatocyte nuclei per 10 HPF (200×). (D) Kaplan-Meier survival curve after hepatectomy in mice with NASH in vehicle- (n = 18) or NSC-treated (n = 12) mice. Statistical analysis was performed using the log rank (Mantel-Cox) test. (E) Representative BrdU immunofluorescence staining in liver sections 72 hours after hepatectomy in vehicle- and NSC-treated NASH mice (n = 3). Scale bar: 100 μm. DAPI-counterstained cells overlayed with BrdU. Quantified BrdU+ hepatocyte nuclei per 10 HPF (200×). (F) Plasma ALT and total bilirubin in NASH mice treated with vehicle or NSC 4 hours after hepatectomy (n = 6–7). (G) Representative image of TUNEL IHC in vehicle or NSC-treated NASH mice 4 hours after hepatectomy with magnified view. Scale bars: 200 μm. TUNEL+ hepatocytes were quantified in 10 HPF (100×) for each mouse (n = 4). Data are shown as mean ± SEM (*P < 0.05, **P < 0.01). Statistical analysis was performed with 2-tailed Student t test, unless otherwise specified.