Theranostics 2019; 9(7):2115-2128. doi:10.7150/thno.30009

Research Paper

Agonist c-Met Monoclonal Antibody Augments the Proliferation of hiPSC-derived Hepatocyte-Like Cells and Improves Cell Transplantation Therapy for Liver Failure in Mice

Lunzhi Yuan1,2*, Yali Zhang1,2*, Xuan Liu1,2,3*, Yao Chen1,2, Liang Zhang1,2, Jiali Cao1,2, Xiaoling Li1,2, Mingfeng Wang1,2, Kun Wu1,2, Jun Zhang1,2, Gang Liu1,3, Qiyi Tang4, Quan Yuan1,2✉, Tong Cheng1,2✉, Ningshao Xia1,2

1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, 361102, PR China
2. National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Science, Xiamen University, Xiamen, 361102, PR China
3. Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen, University, Xiamen 361102, China
4. Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Yuan L, Zhang Y, Liu X, Chen Y, Zhang L, Cao J, Li X, Wang M, Wu K, Zhang J, Liu G, Tang Q, Yuan Q, Cheng T, Xia N. Agonist c-Met Monoclonal Antibody Augments the Proliferation of hiPSC-derived Hepatocyte-Like Cells and Improves Cell Transplantation Therapy for Liver Failure in Mice. Theranostics 2019; 9(7):2115-2128. doi:10.7150/thno.30009. Available from https://www.thno.org/v09p2115.htm

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Abstract

Rationale: Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (hiPSCs) have been developed to address the shortage of primary human hepatocytes (PHHs) for therapeutic applications. However, the in vivo repopulation capacity of HLCs remains limited. This study investigated the roles of agonist antibody activating the c-Met receptor in promoting the in vivo proliferation and repopulation of engrafted PHHs and/or HLCs in mice with liver injuries due to different causes.

Methods: An agonist c-Met receptor antibody (5D5) was used to treat PHHs and hiPSC-HLCs in both cell culture and hepatocyte-engrafted immunodeficient mice mimicking various inherited and acquired liver diseases. The promoting roles and potential influence on the hepatic phenotype of the 5D5 regimen in cell transplantation-based therapeutic applications were systematically evaluated.

Results: In hiPSC-HLC cell cultures, 5D5 treatment significantly stimulated c-Met receptor downstream signalling pathways and accelerated cell proliferation in dose-dependent and reversible manners. In contrast, only slight but nonsignificant promotion was observed in 5D5-treated PHHs. In vivo administration of 5D5 greatly promoted the expansion of implanted hiPSC-HLCs in fumarylacetoacetate hydrolase (Fah) deficient mice, resulting in significantly increased human albumin levels and high human liver chimerism (over 40%) in the transplanted mice at week 8 after transplantation. More importantly, transplantation of hiPSC-HLCs in combination with 5D5 significantly prolonged animal survival and ameliorated liver pathological changes in mice with acute and/or chronic liver injuries caused by Fas agonistic antibody treatment, carbon tetrachloride treatment and/or tyrosinemic stress.

Conclusion: Our results demonstrated that the proliferation of hiPSC-HLCs can be enhanced by antibody-mediated modulation of c-Met signalling and facilitate hiPSC-HLC-based therapeutic applications for life-threatening liver diseases.

Keywords: agonist c-Met receptor, liver failure, cell transplantation, hiPSC-derived hepatocyte-like cells, augmentation of hepatocyte proliferation