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 3

SHP2 inhibition induces a proregenerative transcriptional profile.

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SHP2 inhibition induces a proregenerative transcriptional profile. (A) V...
(A) Venn diagram of differentially regulated genes (–1.5 < log2 fold change > 1.5, FDR < 5%) in murine liver lysates comparing baseline to 40 hours after hepatectomy in vehicle- and NSC-treated mice (n = 3). (B) Common function of IPA canonical pathways significantly changed (–log10 P > 1.3) 40 hours after hepatectomy from baseline in vehicle- and NSC-treated mice. The most common functions identified are listed. The full pathway analysis is provided in Supplemental Table 1. (C) IPA canonical pathway activation scores (Z score) in pathways in which the pathway was significantly changed from baseline (–log10 P > 1.3), and the Z score changed by greater or less than 1 and –1, respectively. (D) Cell cycle gene set heatmap at baseline (vehicle resection specimen) and 40 hours after hepatectomy in mice treated with vehicle or NSC. Each column represents an individual biological replicate. (E) Box and whisker plot (median and IQR) log2FPKM of cell cycle gene transcripts from heatmap in E. (F) Volcano plot comparing gene expression 40 hours after hepatectomy in vehicle- and NSC-treated mice (3 biological replicates/group). Significantly differentially expressed genes (–1.5 < log2FC > 1.5, FDR < 5%) highlighted green (downregulated) and red (upregulated) with top genes identified on plot. Statistical analysis was performed using Wilcoxon rank sum test with continuity correction (E).