Key Points
Endogenous sVEGFR-3 that is expressed by the cornea binds and sequesters VEGF-C and is critical for corneal alymphaticity. sVEGFR-3 overexpression enhances murine corneal graft transplant survival 5-fold by blocking lymphangiogenesis and hemangiogenesis.
The present study examined the extent to which abundance of the prolactin receptor (PRLR) and a range of primary mitochondrial proteins are influenced by either maternal nutrition and/or fetal number in adipose tissue. Pregnant sheep were control fed [consuming 100% of total metabolizable energy (ME) requirements (taking into account requirements for both ewe maintenance and growth of the conceptus to produce a 4.5-kg lamb at term) for that stage of gestation] or were nutrient restricted (consuming 60% of total ME requirements). All ewes lambed normally at term and both perirenal adipose and hepatic tissues were sampled within 6 h of birth. Plasma membranes and mitochondria were prepared and analyzed using immunoblotting for abundance of PRLR and/or cytochrome c, voltage-dependent anion channel (VDAC), and uncoupling protein-1 (UCP1). Irrespective of maternal nutrition, abundance of specific isoforms of PRLR were significantly higher in adipose tissue sampled from twins compared with singletons and total UCP1 concentration per milligram of tissue was increased (p < 0.05). There was no effect of fetal number on PRLR abundance in the liver. Maternal nutrient restriction resulted in an increased abundance of both cytochrome c (p < 0.001) and VDAC in adipose tissue of twins but not singletons. This occurred despite maternal nutrition having no effect on either lamb body or adipose tissue weights, although both were lower (p < 0.05) in twins compared with singletons. In conclusion, fetal adipose tissue development is highly sensitive to nutritionally mediated changes in late gestation. An increase in fetal number results in greater PRLR abundance, which, in conjunction with a decrease in maternal nutrition, results in up-regulation of specific mitochondrial proteins.
Disrupted liver regeneration following hepatectomy 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, mechanism of YAP activation 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. The effects of NSC-87877 were lost in mice with hepatocytespecific Yap/Taz deletion, which 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 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 induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.
Experimental data suggested activation of yes-associated protein (YAP-1) as a critical regulator of liver regeneration (LR). Serotonin (5-HT) promotes LR in rodent models and has been proposed to act via YAP-1. How 5-HT affects LR is incompletely understood. A possible mechanism how 5-HT affects human LR was explored. Sixty-one patients were included. Tissue samples prior and 2 h after induction of LR were collected. Circulating levels of 5-HT and osteopontin (OPN) were assessed. YAP-1, its phosphorylation states, cytokeratin 19 (CK-19) and OPN were assessed using immunofluorescence. A mouse model of biliary epithelial cells (BECs) specific deletion of YAP/TAZ was developed. YAP-1 increased as early as 2 h after induction of LR (p = 0.025) predominantly in BECs. BEC specific deletion of YAP/TAZ reduced LR after 70% partial hepatectomy in mice (Ki67%, p < 0.001). SSRI treatment, depleting intra-platelet 5-HT, abolished YAP-1 and OPN induction upon LR. Portal vein 5-HT levels correlated with intrahepatic YAP-1 expression upon LR (R = 0.703, p = 0.035). OPN colocalized with YAP-1 in BECs and its circulating levels increased in the liver vein 2 h after induction of LR (p = 0.017). In the context of LR tyrosine-phosphorylated YAP-1 significantly increased (p = 0.042). Stimulating BECs with 5-HT resulted in increased YAP-1 activation via tyrosine-phosphorylation and subsequently increased OPN expression. BECs YAP-1 appears to be critical for LR in mice and humans.Our evidence suggests that 5-HT, at least in part, exerts its pro-regenerative effects via YAP-1 tyrosine-phosphorylation in BECs and subsequent OPNdependent paracrine immunomodulation.
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