Evidence against a Stem Cell Origin of New Hepatocytes in a Common Mouse Model of Chronic Liver Injury
Open accessAbstract
Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs) are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.
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Using the Krt19CreERTLSLTdTomato lineage tracing model, the degree of hepatocyte formation from ductular cells in the CDE diet and recovery model is limited.
“Using the the Krt19CreERTLSLTdTomato lineage tracing model we found the degree of hepatocyte formation from ductular cells in the CDE diet and recovery model is limited13, 21, 45;”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [45]
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“Yet, recent studies in mouse models of chronic liver insults indicated that new hepatocytes originated from preexisting hepatocytes, rather than from distinguished nonparenchymal stem-cell populations.((6,7)) One explanation for this ostensible discrepancy might be the capacity of hepatocytes to undergo reversible duc…”
BackgroundHMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
Hernandez, C., Huebener, P., Pradere, J.-P., Antoine, D. J., Friedman, R. A., & Schwabe, R. F. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91786 · Cited by 110 · see citing works
“Despite strong expansion of ductular cells, lineage tracing studies have shown that these cells do not significantly contribute to the generation of functional hepatocytes in the most commonly used models with a “progenitor response”, such as DDC and CDE diet as well as Mdr2 knockout mice, most likely due to the insuf…”
BackgroundLiver progenitor cell-driven liver regeneration
So, J., Kim, A. S., Lee, S., & Shin, D. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0483-0 · Cited by 113 · see citing works
Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases
Kholodenko, I. V., & Yarygin, K. N. (2017) · BioMed Research International · doi:10.1155/2017/8910821 · Cited by 113 · see citing works
Lineage Tracing Reveals the Bipotency of SOX9+ Hepatocytes during Liver Regeneration
Han, X., Wang, Y., Pu, W., Huang, X., Qiu, L., Li, Y., Yu, W., Zhao, H., Liu, X., He, L., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.01.010 · Cited by 113 · see citing works
“However, recent lineage-tracing studies reported that virtually all hepatocytes are derived from pre-existing hepatocytes before injury rather than differentiating from stem cells (Grompe, 2014; Malato et al., 2011; Schaub et al., 2014; Wang et al., 2017; Yanger et al., 2014).”
BackgroundMaladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis
Zhu, C., Tabas, I., Schwabe, R. F., & Pajvani, U. B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00365-6 · Cited by 112 · see citing works
Liver stem cells: experimental findings and implications for human liver disease
Michalopoulos, G. K., & Khan, Z. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.08.004 · Cited by 109 · see citing works
The developing mouse coronal suture at single-cell resolution
Farmer, D. T., Mlčochová, H., Zhou, Y., Koelling, N., Wang, G., Ashley, N., Bugacov, H., Chen, H.-J., Parvez, R. K., Tseng, K.-C., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24917-9 · Cited by 106 · see citing works
Clinical Hepatocyte Transplantation: Practical Limits and Possible Solutions
Gramignoli, R., Vosough, M., Kannisto, K., Srinivasan, R. C., & Strom, S. C. (2015) · European Surgical Research · doi:10.1159/000369552 · Cited by 108 · see citing works
Adaptive remodeling of the biliary architecture underlies liver homeostasis
Kaneko, K., Kamimoto, K., Miyajima, A., & Itoh, T. (2015) · Hepatology · doi:10.1002/hep.27685 · Cited by 108 · see citing works
HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
Khambu, B., Huda, N., Chen, X., Antoine, D. J., Li, Y., Dai, G., Köhler, U. A., Zong, W., Waguri, S., Werner, S., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91814 · Cited by 105 · see citing works
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Chembazhi, U. V., Bangru, S., Hernaez, M., & Kalsotra, A. (2021) · Genome Research · doi:10.1101/gr.267013.120 · Cited by 102 · see citing works
“Several cell-fate and lineage-tracing studies have determined that—under normal circumstances—the majority of new hepatocytes are derived from pre-existing hepatocytes instead of hepatic stem cells (Font-Burgada et al., 2015; Schaub et al., 2014; Yanger et al., 2014).”
BackgroundManco, R., Clerbaux, L.-A., Verhulst, S., Bou Nader, M., Sempoux, C., Ambroise, J., Bearzatto, B., Gala, J. L., Horsmans, Y., van Grunsven, L., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.02.003 · Cited by 92 · see citing works
Ang, C. H., Hsu, S. H., Guo, F., Tan, C. T., Yu, V. C., Visvader, J. E., Chow, P. K. H., & Fu, N. Y. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908099116 · Cited by 102 · see citing works
Cozzolino, A. M., Noce, V., Battistelli, C., Marchetti, A., Grassi, G., Cicchini, C., Tripodi, M., & Amicone, L. (2016) · Stem Cells International · doi:10.1155/2016/5481493 · Cited by 86 · see citing works
“In fact, although the real involvement of liver resident stem/precursor cells in hepatic regeneration after chronic injury is still debated [44–49], it remains extremely important to handle in vitro the differentiation fate of these cells to obtain a source of functional hepatocytes to be used in…”
Switching roles: the functional plasticity of adult tissue stem cells
Wabik, A., & Jones, P. H. (2015) · The EMBO Journal · doi:10.15252/embj.201490386 · Cited by 81 · see citing works
“Lineage tracing in different models of injury indicates surviving hepatocytes re-enter the cell cycle to restore their own lineage (Schaub et al , 2014; Tarlow et al , 2014; Yanger et al , 2014).”
Calcium Signaling in Liver Injury and Regeneration
Oliva‐Vilarnau, N., Hankeová, S., Vorrink, S. U., Mkrtchian, S., Andersson, E. R., & Lauschke, V. M. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00192 · Cited by 84 · see citing works
“Similarly, no labeled hepatocytes were found after pulse labeling of cholangiocytes again suggesting liver regeneration driven by hepatocyte self-replication (115).”
BackgroundAlternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration
Bangru, S., Arif, W., Seimetz, J., Bhate, A., Chen, J., Rashan, E. H., Carstens, R. P., Anakk, S., & Kalsotra, A. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0129-2 · Cited by 85 · see citing works
Liver Stem Cells, Where Art Thou?
Grompe, M. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.08.004 · Cited by 81 · see citing works
“Overall, all four studies (Rodrigo-Torres et al., 2014; Schaub et al., 2014; Tarlow et al., eptember 4, 2014 ª2014 Elsevier Inc. 257 The different methods (red font color) to exclude nonhepatocyte LSPCs as a source of hepatocytes in oval cell injury include nucleoside labeling of rapidly dividing…”
BackgroundMethodInfluentialThe Role of Autophagy for the Regeneration of the Aging Liver
Xu, F., Hua, C., Tautenhahn, H., Dirsch, O., & Dahmen, U. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103606 · Cited by 80 · see citing works
“For example, using the mouse model of chronic liver injury induced by CDE diet, Schaub [93] could not trace hepatocytes which were clearly derived from liver stem cells (LSCs).”
BackgroundMethodCell of origin in biliary tract cancers and clinical implications
Moeini, A., Haber, P. K., & Sia, D. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100226 · Cited by 80 · see citing works
Immune Tolerant Chronic Hepatitis B: The Unrecognized Risks
Kennedy, P. T. F., Litwin, S., Dolman, G. E., Bertoletti, A., & Mason, W. S. (2017) · Viruses · doi:10.3390/v9050096 · Cited by 78 · see citing works
“Importantly, such studies also appear to rule out stem cells in the canals of Hering as a major contributor to hepatocyte replacement, even in cases of extensive liver damage, and suggest instead that proliferating hepatocyte progenitors, which are detected in this situation, are formed by the dedifferentiation of mat…”
BackgroundDiploid hepatocytes drive physiological liver renewal in adult humans
Heinke, P., Rost, F., Rode, J., Trus, P., Simonova, I., Lázár, E., Feddema, J., Welsch, T., Alkass, K., Salehpour, M., et al. (2022) · Cell Systems · doi:10.1016/j.cels.2022.05.001 · Cited by 73 · see citing works
Next-Generation Liver Medicine Using Organoid Models
Akbari, S., Arslan, N., Senturk, S., & Erdal, E. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00345 · Cited by 72 · see citing works
R‐spondin 1 and noggin facilitate expansion of resident stem cells from non‐damaged gallbladders
Lugli, N., Kamileri, I., Keogh, A., Malinka, T., Sarris, M. E., Talianidis, I., Schaad, O., Candinas, D., Stroka, D., & Halazonetis, T. D. (2016) · EMBO Reports · doi:10.15252/embr.201642169 · Cited by 74 · see citing works
“In mice, the contribution of oval cells and, more broadly, liver stem cells to acutely induced liver regeneration is limited [13,14].”
Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis
Lanthier, N., Rubbia‐Brandt, L., Lin-Marq, N., Clément, S., Frossard, J., Goossens, N., Hadengue, A., & Spahr, L. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.04.003 · Cited by 73 · see citing works
“In contrast, other animal studies support the exclusive role of pre-existing hepatocyte replication for liver parenchymal regeneration [15,16].”
ResultStem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration
Carpino, G., Renzi, A., Franchitto, A., Cardinale, V., Onori, P., Reid, L. M., Alvaro, D., & Gaudio, E. (2016) · Stem Cells International · doi:10.1155/2016/3658013 · Cited by 74 · see citing works
Liver regeneration: Cellular origin and molecular mechanisms
Huang, R. C. C., Zhang, X., Gracia‐Sancho, J., & Xie, W. (2022) · Liver International · doi:10.1111/liv.15174 · Cited by 68 · see citing works
Mayer, C. E., Žuklys, S., Zhanybekova, S., Ohigashi, I., Teh, H. Y., Sansom, S. N., Shikama‐Dorn, N., Hafen, K., Macaulay, I. C., Deadman, M. E., et al. (2015) · European Journal of Immunology · doi:10.1002/eji.201545995 · Cited by 67 · see citing works
Adult Mouse Liver Contains Two Distinct Populations of Cholangiocytes
Li, B., Dorrell, C., Canaday, P. S., Pelz, C., Haft, A., Finegold, M. J., & Grompe, M. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.06.003 · Cited by 66 · see citing works
“9 j 478–489 j August 8, 2017 j a 2017 The Auth This is an open access article under the CC BY-NC-ND license (http://creativ et al., 2012; Schaub et al., 2014; Tarlow et al., 2014a, 2014b; Yanger et al., 2013).”
BackgroundLiu, K., Jin, H., & Zhou, B. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011631 · Cited by 69 · see citing works
“Other studies report that the newly generated hepatocytes are derived from pre-existing hepatocytes after injury (70-74).”
BackgroundCellular and molecular basis of liver regeneration
Bangru, S., & Kalsotra, A. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.12.004 · Cited by 66 · see citing works
Hepatic Progenitor Cells in Action
Kaur, S., Siddiqui, H., & Bhat, M. H. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.06.004 · Cited by 65 · see citing works
Organoids from adult liver and pancreas: Stem cell biology and biomedical utility
Hindley, C. J., Cordero-Espinoza, L., & Huch, M. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.06.039 · Cited by 65 · see citing works
“However, a biliary origin for the oval cell has recently been challenged by data from the Willenbring and Stanger labs using viral-mediated Cre lineage tracing, which convincingly demonstrates that the repair of the damaged liver relies predominantly on the hepatocyte compartment [26, 40].”
BackgroundMatsumoto, T., Takai, A., Eso, Y., Kinoshita, K., Manabe, T., Seno, H., Chiba, T., & Marusawa, H. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1800 · Cited by 64 · see citing works
“On the other hand, whether hepatocytes are regenerated 17 from PDCs in chronically damaged liver remains controversial (6-11).”
Regulation of hepatocyte identity and quiescence
Berasain, C., & Avila, M. A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1970-7 · Cited by 62 · see citing works
“Genetic fate tracing experiments in adult mice with chronic liver injury failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells; in fact, no hepatocytes were detected that were not derived from preexisting hepatocytes [120].”
BackgroundHuman liver organoids: From generation to applications
Afonso, M. B., Marques, V., van Mil, S. W. C., & Rodrigues, C. M. P. (2024) · Hepatology · doi:10.1097/hep.0000000000000343 · Cited by 61 · see citing works
“[8] 19 – 21] Based on these findings, attempts were also made to generate protocols to grow organoids from primary hepatocytes.”
BackgroundAure, M. H., Arany, S., & Ovitt, C. E. (2015) · Journal of Dental Research · doi:10.1177/0022034515599770 · Cited by 61 · see citing works
“Studies have demonstrated that mature hepatocytes self-renew under normal conditions, as well as regenerate or even transdifferentiate following injury (Yanger et al. 2013; Schaub et al. 2014; Tanimizu et al. 2014; Tarlow et al. 2014; Yanger et al. 2014).”
Wang, S., Miller, S. R., Ober, E. A., & Sadler, K. C. (2017) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.11.012 · Cited by 61 · see citing works
“This is supported by lineage tracing experiments in a range of chemically induced liver damage (Schaub et al., 2014; Yanger et al., 2014).”
BackgroundMolecular pathways of liver regeneration: A comprehensive review
Kiseleva, Y. V., Antonyan, S. Z., Zharikova, T. S., Tupikin, K. A., Kalinin, D. V., & Zharikov, Y. O. (2021) · World Journal of Hepatology · doi:10.4254/wjh.v13.i3.270 · Cited by 62 · see citing works
Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis
Overi, D., Carpino, G., Franchitto, A., Onori, P., & Gaudio, E. (2020) · Cells · doi:10.3390/cells9030590 · Cited by 61 · see citing works
“Similarly, recent evidence have further disclosed the dynamics of hepatocyte replication in physiological turnover and in regeneration after injury, demonstrating that most hepatocytes throughout the lobule participate in maintaining the hepatocyte mass and proliferate to regenerate it, with diploid cells holding a gr…”
BackgroundLu, J., Zhou, Y., Hu, T., Zhang, H., Shen, M., Cheng, P., Dai, W., Wang, F., Chen, K., Zhang, Y., et al. (2016) · Scientific Reports · doi:10.1038/srep22754 · Cited by 59 · see citing works
Regenerative Biology of Tendon: Mechanisms for Renewal and Repair
Dyment, N. A., & Galloway, J. L. (2015) · Current Molecular Biology Reports · doi:10.1007/s40610-015-0021-3 · Cited by 59 · see citing works
Rizvi, F., Lee, Y., Díaz‐Aragon, R., Bawa, P., So, J., Florentino, R. M., Wu, S. Y., Sarjoo, A., Truong, E., Smith, A. R., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.10.008 · Cited by 59 · see citing works
Kuijk, E., Rasmussen, S. A., Blokzijl, F., Huch, M., Gehart, H., Toonen, P. W., Begthel, H., Clevers, H. C., Geurts, A. M., & Cuppen, E. P. J. G. (2016) · Scientific Reports · doi:10.1038/srep22154 · Cited by 56 · see citing works
The Hippo pathway in cellular reprogramming and regeneration of different organs
Moya, I. M., & Halder, G. A. (2016) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2016.08.004 · Cited by 56 · see citing works
Liver regeneration in aged mice: new insights
Pibiri, M. (2018) · Aging · doi:10.18632/aging.101524 · Cited by 57 · see citing works
Cholangiopathies – Towards a molecular understanding
Tam, P. K. H., Yiu, R. S. W., Lendahl, U., & Andersson, E. R. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.08.024 · Cited by 54 · see citing works
Road to stemness in hepatocellular carcinoma
Flores-Téllez, T. D. N. J., Villa‐Treviño, S., & Piña‐Vázquez, C. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i37.6750 · Cited by 51 · see citing works
Yin, C. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.08.015 · Cited by 50 · see citing works
Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration
Ko, S., Choi, T., Russell, J. O., So, J., Monga, S. P., & Shin, D. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.10.017 · Cited by 48 · see citing works
“However, recent lineage tracing studies in mice reveal that pre-existing hepatocytes are the main source of regenerated hepatocytes in current oval cell activation models [3,4], raising a controversy about BEC-driven liver regeneration.”
BackgroundMethodThe plastic cellular states of liver cells: Are EpCAM and Lgr5 fit for purpose?
Huch, M., & Dollé, L. (2016) · Hepatology · doi:10.1002/hep.28469 · Cited by 48 · see citing works
“On the other hand, reports using virusmediated Cre lineage-tracing approaches have recently ruled out the existence of progenitor-driven regeneration in the mouse.((25,26)) One explanation for this paradox could be that liver pathologies in these models are not sufficiently severe, so remaining “healthy” hepatocytes c…”
BackgroundHepatic progenitor cell activation in liver repair
Bria, A., Marda, J., Zhou, J., Sun, X., Cao, Q., Petersen, B. E., & Pi, L. (2017) · Liver Research · doi:10.1016/j.livres.2017.08.002 · Cited by 48 · see citing works
Fetal liver development and implications for liver disease pathogenesis
Lotto, J., Stephan, T. L., & Hoodless, P. A. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00775-2 · Cited by 47 · see citing works
Kamimoto, K., Nakano, Y., Kaneko, K., Miyajima, A., & Itoh, T. (2020) · Communications Biology · doi:10.1038/s42003-020-1006-1 · Cited by 46 · see citing works
Nikolaou, K. C., Moulos, P., Chalepakis, G., Hatzis, P., Oda, H., Reinberg, D., & Talianidis, I. (2014) · The EMBO Journal · doi:10.15252/embj.201489279 · Cited by 45 · see citing works
“This possibility is also supported by recent studies demonstrating that existing hepatocytes and not progenitors generate new hepatocytes in different injury-mediated liver regeneration models (Schaub et al, 2014; Yanger et al, 2014).”
ResultOrganizational Principles of the Liver
Nagy, P., Thorgeirsson, S., & Grisham, J. (2020) · doi:10.1002/9781119436812.ch1 · Cited by 39 · see citing works
- Authors
- Schaub, J. R., Malato, Y., Gormond, C., & Willenbring, H.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Willenbring, Holger
- ORCID
- Willenbring, Holger
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 8
- Issue
- 4
- Pages
- 933-939
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4376310
- OpenAlex
- W2023821363
- Cited by
- 254
- References
- 31
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 5 · 2023: 13 · 2022: 9 · 2021: 14 · 2020: 24 · 2019: 23 · 2018: 39 · 2017: 30 · 2016: 36 · 2015: 39 · 2014: 10
- FWCI
- 21.47
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-09-11)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK26743, P30DK026743, T32DK060414)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver stem cells, hepatocyte regeneration, chronic liver injury, choline-deficient ethionine-supplemented diet, cholangiocytes, hepatocyte proliferation, liver regeneration
- MeSH terms
- Animals, Liver, Liver Regeneration, Mice, Transgenic, Cell Lineage, Hepatocytes, Chemical and Drug Induced Liver Injury, Chronic, Mesenchymal Stem Cells
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