Abstract
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/β-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 undefined. 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, Wnt5a, Wnt9b, Wnt10a and Wnt10b, are highly expressed concordantly with the high levels of canonical Wnts in late stages of liver tissues. Wnt5a, Wnt9b, Wnt10a and Wnt10b are able to antagonize Wnt3a-induced β-catenin/TCF activity, reduce the stemness of iHPx cells, and promote hepatic differentiation of liver progenitors. Stem cell implantation assay demonstrates that Wnt5a, Wnt9b, Wnt10a and Wnt10b can inhibit cell proliferation and promote hepatic differentiation of the iHPx progenitor cells. Our results strongly suggest that noncanonical Wnts may play an important role in fine-tuning Wnt/β-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.
Highlights
As the largest internal organ and gland in the body, the liver provides vital metabolic, exocrine and endocrine functions, including secretion of several hormones such as insulin-like growth factors, angiotensinogen and thrombopoietin, production of bile, metabolism of dietary compounds, regulation of cholesterol synthesis and transport, urea metabolism, drug detoxification, regulation of glucose levels through glycogen storage, and control of blood homeostasis by secretion of clotting factors and serum proteins such as albumin and apolipoproteins [1,2,3]
Our results strongly suggest that noncanonical Wnts may play an important role in fine-tuning Wnt/β-catenin functions during liver development and liver regeneration
The biological roles of several canonical Wnts and β-catenin signaling in liver development and hepatocellular tumorigenesis have been extensively studied [15, 17], it remains to be fully understood about how canonical Wnt signaling is modulated under physiological and/or pathological conditions of the liver
Summary
As the largest internal organ and gland in the body, the liver provides vital metabolic, exocrine and endocrine functions, including secretion of several hormones such as insulin-like growth factors, angiotensinogen and thrombopoietin, production of bile, metabolism of dietary compounds, regulation of cholesterol synthesis and transport, urea metabolism, drug detoxification, regulation of glucose levels through glycogen storage, and control of blood homeostasis by secretion of clotting factors and serum proteins such as albumin and apolipoproteins [1,2,3]. The liver has long been speculated to harbor facultative stem cells that can become activated if the injury impairs the ability of the mature cells, especially hepatocytes, to replicate [4, 5]. These facultative stem cells are believed to reside near the portal region of the hepatic lobule in the canal of Hering [4, 5]. The hepatic stem cells may proliferate and produce ‘oval cells’, intermediate cells that have properties of both bile ducts and hepatocytes, which would differentiate into functional mature hepatocytes [4, 5]. Harnessing the regulatory mechanisms that control the proliferation and differentiation of liver progenitor cells may hold great promise to facilitating liver regeneration and/or progenitor cell-based therapies for liver diseases [5]
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