The Hippo signaling pathway has been shown by our laboratory and others to be a critical growth and tumor suppressor pathway in the mammalian liver. Furthermore, we have shown that Hippo signaling plays an important role in suppressing activation of a facultative adult liver stem cell population that is often mobilized in response to liver injury in both mice and humans. Despite its importance in maintaining adult liver homeostasis, the role of Hippo signaling in regulating embryonic liver progenitor cell development has not been explored. We now have preliminary data indicating that Hippo signaling plays distinct roles in the development of the two major cell types of the liver: hepatocytes and biliary epithelial cells. In hepatocytes, Hippo signaling is activated to ensure proper functioning of these cells, whereas in biliary epithelial cells, Hippo signaling appears to be dampened, allowing the Hippo pathway transcriptional co---activators Yap and Taz to direct biliary epithelial cell fate and differentiation. In this proposal we will explore mechanisms that regulate Hippo signaling in hepatocytes and biliary epithelial cells and define the transcriptional programs impacted by Hippo signaling and how Hippo signaling interfaces with the chromatin landscape to direct liver progenitor cell development. Furthermore, we have conducted an in vivo genetic screen for novel regulators of Hippo signaling and we propose to study these novel Hippo pathway regulators in the context of liver progenitor cell development. Taken together, our proposed studies will advance research on lineage---specific stem cell self-renewal, proliferation, and differentiation and provide novel insights into regulation of the Hippo signalin pathway.
We have found that the recently described Hippo signaling pathway plays a critical role in modulating hepatocyte and biliary epithelial cell differentiation from bipotential fetal hepatic progenitor cells. In the proposed research we will explore mechanisms that control liver progenitor cell development by the Hippo signaling pathway and identify novel regulators of Hippo signaling that impact liver progenitor cell differentiation. Thee studies will provide new avenues for more efficient ex vivo manipulation of liver progenitor cells for use in cell-based therapies.