Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice

• DOI: 10.1002/hep.26511
• Publication Date: 2013-05-23T22:05:10Z
• Authors: Guanhua Xie; Gamze Karaca; Marzena Swiderska...; Gregory A. Michel...; Leandi Krüger; Yuping Chen; Richard T. Premont; Steve S. Choi; Anna Mae Diehl
• Keywords: Hepatic stellate cell; Cell fate determination

Liver repair involves phenotypic changes in hepatic stellate cells (HSCs) and reactivation of morphogenic signaling pathways that modulate epithelial-to-mesenchymal/mesenchymal-to-epithelial transitions, such as Notch Hedgehog (Hh). Hh stimulates HSCs to become myofibroblasts (MFs). Recent lineage tracing studies adult mice with injured livers showed some MFs became multipotent progenitors regenerate hepatocytes, cholangiocytes, HSCs. We studied primary HSC cultures two different animal models fibrosis evaluate the hypothesis activating pathway them (and remain) through a mechanism an epithelial-to-mesenchymal–like transition requires cross-talk canonical pathway. found when cultured transitioned into MFs, they activated signaling, underwent transition, increased signaling. Blocking MFs/HSCs suppressed activity caused mesenchymal-to-epithelial–like transition. Inhibiting also induced Manipulating mouse progenitor cell line evoked similar responses. In mice, liver injury Hh-responsive MF progeny (i.e., ductular cells). Conditionally disrupting bile-duct–ligated inhibited blocked accumulation both cells. Conclusions: The interact control fate key types involved by modulating epithelial-to-mesenchymal–like/mesenchymal-to-epithelial–like transitions. (Hepatology 2013;58:1801–1813)