We found that when cultured HSCs transitioned into MFs, they activated Hh signaling, underwent an epithelial-to-mesenchymal–like

transition, and increased Notch signaling. Blocking Notch signaling in MFs/HSCs suppressed Hh activity and caused a mesenchymal-to-epithelial–like transition. Inhibiting the Hh pathway suppressed Notch signaling and also induced a mesenchymal-to-epithelial–like transition. Manipulating Hh and Notch signaling in a mouse multipotent progenitor cell line evoked similar responses. In mice, liver injury increased Notch activity in MFs and Hh-responsive MF progeny (i.e., HSCs and ductular cells). Y-27632 mw Conditionally disrupting Hh signaling in MFs of bile-duct–ligated check details mice inhibited Notch signaling and blocked accumulation of both MF and ductular cells. Conclusions: The Notch and Hedgehog pathways interact to control the fate of key cell types involved in adult liver repair by modulating epithelial-to-mesenchymal–like/mesenchymal-to-epithelial–like transitions.

(Hepatology 2013;58:1801–1813) The outcome of liver injury is dictated by the efficiency of repair responses that replace damaged liver tissue with healthy hepatic parenchyma. Defective repair of chronic liver injury can result in cirrhosis, a scarring condition characterized

by dramatic changes in the cellular composition of the liver. Outgrowth of progenitors and myofibroblasts (MFs) is particularly prominent during scarring.[1] Because these cell types are Glutamate dehydrogenase critical for successful regeneration of damaged livers,[1, 2] their accumulation in cirrhotic liver suggests that scarring may occur because regenerative mechanisms become stalled prematurely. Therefore, to restore healthy wound healing, it is necessary to characterize and prioritize the key signals that regulate the fate of cells that are required for liver repair. Reconstruction of damaged adult liver utilizes several highly conserved signaling pathways that orchestrate organogenesis during fetal development, including Wnt, Hedgehog (Hh), and Notch.[3] During embryogenesis, these pathways interact to modulate survival, proliferation, and differentiation of their target cells so that developing organs become appropriately populated with all of the cell types necessary for tissue-specific functions. For example, cross-talk between Hh and Notch controls the fate of embryonic stem cells,[4] zebrafish neural progenitors,[5] and Drosophila eye precursors.[6] In cancer biology, the importance of cell-autonomous cross-talk between Hh and Notch is also emerging.