| Background: The liver provides vital metabolic,exocrine and endocrine functions in the body as such pathological conditions of the liver lead to high morbidity and mortality.The liver is highly regenerative and contains facultative stem cells that become activated during injury to replicate to fully recover mass and function.Canonical Wnt/?-catenin signaling plays an important role in regulating the proliferation and differentiation of liver progenitor cells during liver regeneration.However,possible roles of noncanonical Wnts in liver development and regeneration remain undefned.Objective: To understand the possible roles of noncanonical Wnts in liver development and regeneration.Method:We previously established a reversibly-immortalized hepatic progenitor cell line(iHPx),which retains hepatic differentiation potential.Here,we analyze the expression pattern of the essential components of both canonical and noncanonical Wnt signaling pathways at different postnatal stages of mouse liver tissues and iHPx cells.We find that noncanonical Wnt4,Wnt5 a,Wnt9b,Wnt10 a and Wnt10 b,are highly expressed concordantly with the high levels of canonical Wnts in late stages of liver tissues.Wnt5 a,Wnt9b,Wnt10 a and Wnt10 b are able to antagonize Wnt3a-induced ?-catenin/TCF activity,reduce the stemness of iHPx cells,and promote hepatic differentiation of liver progenitors.Stem cell implantation assay demonstrates that Wnt5 a,Wnt9b,Wnt10 a and Wnt10 b can inhibit cell proliferation and promote hepatic differentiation of the iHPx progenitor cells.Result: Our results strongly suggest that noncanonical Wnts may play an important role in fne-tuning Wnt/?-catenin functions during liver development and liver regeneration.Thus,understanding regulatory mechanisms governing proliferation and differentiation of liver progenitor cells may hold great promise to facilitate liver regeneration and/or progenitor cell-based therapies for liver diseases. |
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