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The role of Hippo signaling in liver regeneration

Boek - Dissertatie

According to the current dogma, the Hippo pathway is a major regulator of organ growth and regeneration. In this model, Hippo pathway effectors YAP and TAZ directly drive cell proliferation during organ growth and regeneration by promoting the expression of target genes involved in cell proliferation. This idea is largely based on results from gain-of-function experiments, which showed that artificial activation of YAP/TAZ is sufficient to trigger ectopic cell proliferation and dramatic overgrowth in many organs including the liver. Notably, however, tissue-specific deletion of Yap and Taz was inconsequential for cell proliferation during developmental liver growth. Similarly, the role of YAP and TAZ in regenerative growth is unclear, and many questions remain until this day. We and others found that YAP is transiently activated in hepatocytes in response to liver injury. In addition, loss of Yap/Taz in the regenerating liver resulted in regeneration defects. These observations, in combination with the massive proliferative reaction in gain-of-function studies, led to the assumption that YAP/TAZ are required to drive hepatocyte proliferation during regeneration. However, we provide evidence that YAP and TAZ are not essential in regenerating hepatocytes. Instead, we show that impaired liver regeneration is a consequence of Yap/Taz knockout in biliary epithelial cells (BECs), where they play an essential role in development and maintenance. Since the used knockout model causes gene deletion simultaneously in embryonic hepatocytes and BECs, we aimed to distinguish YAP/TAZ functions in hepatocytes from their functions in BECs using knockout models separately targeting each of these cell types. An in-depth characterization of several BEC-specific knockout mouse models was first performed to choose the most appropriate model. Surprisingly, regenerative defects were observed in BEC-specific Yap/Taz knockout mice, but not in hepatocyte-specific knockouts. The defects appear to be secondary effects of bile duct disruption and cholestasis, which arises as a consequence of Yap/Taz deletion in BECs. Our data suggests that cholestasis impairs the recruitment and activation of macrophages through PXR signaling, thereby delaying the clearance of necrotic cell corpses after toxic injury. The presence or absence of YAP/TAZ in hepatocytes does not affect this regeneration process. In conclusion, we did not observe a regeneration-specific function for YAP/TAZ in the liver after toxic injury, but instead uncovered an important role for BEC maintenance which, when lost, has far-reaching consequences on homeostasis and regeneration in the whole organ. Since the generally accepted hypothesis for YAP/TAZ as master regulators of growth was largely based on incorrectly interpreted phenotypes in the liver, endogenous YAP/TAZ functions might differ between organs and should be reassessed in a tissue- and cell type-specific manner. Indeed, our study reveals highly surprising results that will force a fundamental change in how we think about the function of the Hippo pathway, not only in regeneration, but in growth control in general.
Jaar van publicatie:2020
Toegankelijkheid:Open