Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2018; 10(2): 213-221
Published online Feb 27, 2018. doi: 10.4254/wjh.v10.i2.213
Cell fusion in the liver, revisited
Michela Lizier, Alessandra Castelli, Cristina Montagna, Franco Lucchini, Paolo Vezzoni, Francesca Faggioli
Michela Lizier, Alessandra Castelli, Paolo Vezzoni, Francesca Faggioli, Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
Michela Lizier, Alessandra Castelli, Paolo Vezzoni, Francesca Faggioli, Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
Cristina Montagna, Department of Genetics and Pathology Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, United States
Franco Lucchini, Centro Ricerche Biotecnologiche, Università Cattolica del Sacro Cuore, Cremona 26100, Italy
Author contributions: Montagna C, Lucchini F, Vezzoni P and Faggioli F conceived the study design and wrote the paper; Lucchini F coordinated the new experiments in mice; Lizier M and Faggioli F produced and analyzed the chimeric mice; Castelli A performed molecular analysis; All the authors participated in the interpretation of the new results.
Supported by Grant AMANDA “Alterazioni metaboliche, stress cellulari e processi neurodegenerativi” from Regione Lombardia/CNR Project to P.V. Castelli A is a recipient of a fellowship from Fondazione Nicola del Roscio.
Conflict-of-interest statement: The authors declare no competing financial interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Francesca Faggioli, PhD, Research Scientist, Istituto di Ricerca Genetica e Biomedica, CNR, via Fantoli 15/16, Milan 20138, Italy.
Telephone: +39-2-82245158 Fax: +39-2-82245190
Received: November 21, 2017
Peer-review started: November 23, 2017
First decision: December 18, 2017
Revised: December 28, 2017
Accepted: February 5, 2018
Article in press: February 5, 2018
Published online: February 27, 2018

There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show “transdifferentiation”, but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear.

Keywords: Cell fusion, Hepatocytes, TdTomato, Lineage tracing, Chimeras, Extracellular vesicles

Core tip: About 70% of hepatocytes are polyploid, arising either from genome duplication without division (endoreplication) or from cell fusion. Experiments with chimeric mice containing two cell populations each bearing a different genetic marker had shown that some liver cells express markers of both genomes, suggesting that cell fusion occurred. Here, we review the data in the literature and describe new experiments using a chimeric model that confirms that cell fusion contributes to liver polyploidy. We argue that the role of cell fusion in pathological conditions, such as viral hepatitis and neoplastic transformation, is worth further study.