Noncanonical Wnt signaling plays an important role in modulating canonical Wnt-regulated stemness, proliferation and terminal differentiation of hepatic progenitors

// Jiaming Fan 1, 2, * , Qiang Wei 2, 3, * , Junyi Liao 2, 3 , Yulong Zou 1, 2 , Dongzhe Song 2, 4 , Dongmei Xiong 1 , Chao Ma 2, 5 , Xue Hu 2, 3 , Xiangyang Qu 2, 3 , Liqun Chen 2, 3 , Li Li 2, 6 , Yichun Yu 2, 7 , Xinyi Yu 2, 3 , Zhicai Zhang 2, 8 , Chen Zhao 2, 3 , Zongyue Zeng 2, 3 , Ruyi Zhang 2, 3 , Shujuan Yan 2, 3 , Tingting Wu 2, 5 , Xingye Wu 2, 3 , Yi Shu 2, 3 , Jiayan Lei 2, 3 , Yasha Li 2, 3 , Wenwen Zhang 2, 9 , Rex C. Haydon 2 , Hue H. Luu 2 , Ailong Huang 1 , Tong-Chuan He 2 , Hua Tang 1 1 Key Laboratory of Molecular Biology for Infectious Diseases of The Ministry of Education of China, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China 2 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA 3 Ministry of Education Key Laboratory of Diagnostic Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing, China 4 Department of Conservative Dentistry and Endodontics, West China Hospital and West China School of Stomatology, Sichuan University, Chengdu, China 5 Departments of Neurosurgery and Otolaryngology-Head & Neck Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China 6 Department of Biomedical Engineering, School of Bioengineering, Chongqing University, Chongqing, China 7 Department of Emergency Medicine, Beijing Hospital, Beijing, China 8 Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China 9 Department of Laboratory Medicine and Clinical Diagnostics, The Affiliated Yantai Hospital, Binzhou Medical University, Yantai, China * These authors have contributed equally to this work Correspondence to: Tong-Chuan He, email: tche@uchicago.edu Hua Tang, email: tanghua86162003@cqmu.edu.cn Keywords: Wnt/β-catenin, noncanonical Wnt signaling, liver stem cells, liver cancer, liver regeneration Received: December 07, 2016 Accepted: January 24, 2017 Published: February 23, 2017 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.