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Next-Generation Hepatocyte Expansion: Bridging Molecular Reprogramming with Multicellular Organoids for Clinical Translation.

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Title: Next-Generation Hepatocyte Expansion: Bridging Molecular Reprogramming with Multicellular Organoids for Clinical Translation.
Authors: Zhou Y; Department of Hepatobiliary Surgery II, Guangdong Engineering Technology Research Center of Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China., Zeng M; Department of Hepatobiliary Surgery II, Guangdong Engineering Technology Research Center of Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China., Fu G; Department of Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China. mhksfgb@126.com., Gao Y; Department of Hepatobiliary Surgery II, Guangdong Engineering Technology Research Center of Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. gaoyi6146@163.com.; State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, China. gaoyi6146@163.com.; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Southern Medical University, Guangzhou, China. gaoyi6146@163.com.
Source: Stem cell reviews and reports [Stem Cell Rev Rep] 2026 Aug; Vol. 22 (6), pp. 2752-2767. Date of Electronic Publication: 2026 Jun 16.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: Springer Country of Publication: United States NLM ID: 101752767 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2629-3277 (Electronic) Linking ISSN: 26293277 NLM ISO Abbreviation: Stem Cell Rev Rep Subsets: MEDLINE
Imprint Name(s): Publication: 2011- : [New York, NY] : Springer
Original Publication: [Totowa, N.J.] : Humana Press, [2009]-
MeSH Terms: Hepatocytes*/cytology , Hepatocytes*/metabolism , Hepatocytes*/transplantation , Organoids*/cytology , Organoids*/metabolism , Translational Research, Biomedical* , Cellular Reprogramming*, Humans ; Animals ; Cell Proliferation
Abstract: Orthotopic liver transplantation (OLT) remains the gold standard treatment for end-stage liver disease but is severely limited by donor scarcity and immune rejection. Consequently, bioartificial liver (BAL) systems and hepatocyte transplantation have emerged as promising alternatives, yet their clinical efficacy hinges on the unresolved challenge of generating functional hepatocytes at scale. This review systematically examines the molecular landscape governing hepatocyte proliferation, dissecting the key regulatory roles of Wnt/β-catenin, Hippo-YAP, Notch, and TGF-β signaling pathways in balancing proliferation and differentiation. We critically evaluate current in vitro expansion strategies, contrasting viral-mediated genetic modification approaches with emerging non-genome-editing strategies. Particular emphasis is placed on "next-generation" methodologies, including chemically defined media, bioreactor-based dynamic cultures, and multicellular co-culture systems that recapitulate the native hepatic niche. Furthermore, we highlight recent breakthroughs in liver organoid technology-such as the construction of multi-zonal and vascularized architectures-that bridge the gap between in vitro expansion and in vivo physiological relevance. Finally, we summarize the translational progress of these expanded hepatocytes in BAL devices, cell transplantation trials, and high-fidelity pharmacotoxicological models. We further discuss how emerging technologies, including CRISPR-Cas9-mediated gene correction and bioengineering innovations, may help address current limitations, while acknowledging that substantial preclinical validation remains necessary.
(© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Consent for Publication Clinical Trial Number: Not applicable. Competing interests: The authors declare no competing interests.
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Grant Information: 2025B1111110001 Guangdong S&T Program; 2022YFA1104900 National Key R&D Program of China; 92068206 National Nature Science Foundation of China
Contributed Indexing: Keywords: Bioartificial liver (BAL); Cell-based therapy; Hepatocyte expansion; Liver organoids; Liver regeneration
Entry Date(s): Date Created: 20260616 Date Completed: 20260710 Latest Revision: 20260710
Update Code: 20260711
DOI: 10.1007/s12015-026-11172-y
PMID: 42301605
Database: MEDLINE
Description
ISSN:2629-3277
DOI:10.1007/s12015-026-11172-y