Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver
Open accessAbstract
Background: Stem/progenitor cell niches in tissues regulate stem/progenitor cell differentiation and proliferation through local signalling. Objective: To examine the composition and formation of stem progenitor cell niches. Methods: The composition of the hepatic progenitor cell niche in independent models of liver injury and hepatic progenitor cell activation in rodents and humans was studied. To identify the origin of the progenitor and niche cells, sex-mismatched bone marrow transplants in mice, who had received the choline–ethionine-deficient-diet to induce liver injury and progenitor cell activation, were used. The matrix surrounding the progenitor cells was described by immunohistochemical staining and its functional role controlling progenitor cell behaviour was studied in cell culture experiments using different matrix layers. Results: The progenitor cell response in liver injury is intimately surrounded by myofibroblasts and macrophages, and to a lesser extent by endothelial cells. Hepatic progenitor cells are not of bone marrow origin; however, bone marrow-derived cells associate intimately with these cells and are macrophages. Laminin always surrounds the progenitor cells. In vitro studies showed that laminin aids maintenance of progenitor and biliary cell phenotype and promotes their gene expression (Dlk1, Aquaporin 1, γGT) while inhibiting hepatocyte differentiation and gene expression (CEPB/α). Conclusions: During liver damage in rodents and humans a stereotypical cellular and laminin niche forms around hepatic progenitor cells. Laminin helps maintenance of undifferentiated progenitor cells. The niche links the intrahepatic progenitor cells with bone marrow-derived cells and links tissue damage with progenitor cell-mediated tissue repair.
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Fn14 has been identified as a critical receptor for mitogenic stimulation of HPCs.
“Fn14 has been identified as a critical receptor for mitogenic stimulation of HPCs31-34.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [31]
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Cites
Bone Marrow as a Potential Source of Hepatic Oval Cells
Petersen, B. E., Bowen, W. C., Patrene, K. D., Mars, W. M., Sullivan, A. K., Murase, N., Boggs, S. S., Greenberger, J. S., & Goff, J. P. (1999) · Science · doi:10.1126/science.284.5417.1168 · Cited by 2,377 · see citing works
The relationship between the spleen colony-forming cell and the haemopoietic stem cell.
Schofield, R. (1978) · PubMed · Cited by 2,319 · see citing works
Socializing with the Neighbors
Fuchs, E. V., Tumbar, T., & Guasch, G. (2004) · Cell · doi:10.1016/s0092-8674(04)00255-7 · Cited by 1,711 · see citing works
Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair
Duffield, J. S., Forbes, S. J., Constandinou, C. M., Clay, S., Partolina, M., Vuthoori, S., Wu, S., Lang, R., & Iredale, J. P. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200522675 · Cited by 1,649 · see citing works
Self-citationSpradling, A. C., Drummond‐Barbosa, D., & Kai, T. (2001) · Nature · doi:10.1038/35102160 · Cited by 1,429 · see citing works
A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells
Lee, J., Heo, J., Libbrecht, L. J., Chu, I., Kaposi-Novák, P., Calvisi, D. F., Mikaelyan, A. S., Roberts, L. R., Demetris, A. J., Sun, Z., et al. (2006) · Nature Medicine · doi:10.1038/nm1377 · Cited by 953 · see citing works
A Niche Maintaining Germ Line Stem Cells in the Drosophila Ovary
Xie, T., & Spradling, A. C. (2000) · Science · doi:10.1126/science.290.5490.328 · Cited by 765 · see citing works
Roskams, T., Theise, N. D., Balabaud, C. P., Bhagat, G., Bhathal, P. S., Bioulac‐Sage, P., Brunt, E. M., Crawford, J. M., Crosby, H. A., Desmet, V. J., et al. (2004) · Hepatology · doi:10.1002/hep.20130 · Cited by 729 · see citing works
The canals of hering and hepatic stem cells in humans
Theise, N. D., Saxena, R., Portmann, B. C., Thung, S. N., Yee, H. T., Chiriboga, L. A., Kumar, A., & Crawford, J. M. (1999) · Hepatology · doi:10.1002/hep.510300614 · Cited by 700 · see citing works
Chiba, T., Kita, K., Zheng, Y., Yokosuka, O., Saisho, H., Iwama, A., Nakauchi, H., & Taniguchi, H. (2006) · Hepatology · doi:10.1002/hep.21227 · Cited by 664 · see citing works
The Bone Marrow Functionally Contributes to Liver Fibrosis
Russo, F. P., Alison, M. R., Bigger, B., Amofah, E., Florou, A., Amin, F., Bou–Gharios, G., Jeffery, R. E., Iredale, J. P., & Forbes, S. J. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.01.036 · Cited by 483 · see citing works
Self-citationFallowfield, J. A., Mizuno, M., Kendall, T. J., Constandinou, C. M., Benyon, R. C., Duffield, J. S., & Iredale, J. P. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.5288 · Cited by 479 · see citing works
Self-citationA significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis☆
Forbes, S. J., Russo, F. P., Rey, V., Burra, P., Rugge, M., Wright, N. A., & Alison, M. R. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.02.025 · Cited by 436 · see citing works
Self-citationA conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans
Crittenden, S. L., Bernstein, D. S., Bachorik, J. L., Thompson, B. E., Gallegos, M. E., Petcherski, A. G., Moulder, G. L., Barstead, R. J., Wickens, M., & Kimble, J. E. (2002) · Nature · doi:10.1038/nature754 · Cited by 421 · see citing works
Progenitor Cells in Diseased Human Liver
Roskams, T., Libbrecht, L. J., & Desmet, V. J. (2003) · Seminars in Liver Disease · doi:10.1055/s-2004-815564 · Cited by 337 · see citing works
Role of cholangioles in restoration of the liver of the mouse after dietary injury
Wilson, J. W., & Leduc, E. H. (1958) · The Journal of Pathology and Bacteriology · doi:10.1002/path.1700760213 · Cited by 184 · see citing works
Activation of stem cells in hepatic diseases
Bird, T. G., Lorenzini, S., & Forbes, S. J. (2007) · Cell and Tissue Research · doi:10.1007/s00441-007-0542-z · Cited by 170 · see citing works
Self-citationThe vascular niche and its basement membrane
Nikolova, G. V., Strilić, B., & Lammert, E. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.11.005 · Cited by 157 · see citing works
Oh, S., Witek, R. P., Bae, S., Zheng, D., Jung, Y., Piscaglia, A. C., & Petersen, B. E. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.01.001 · Cited by 147 · see citing works
Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation
Nguyen, L., Furuya, M. H., Wolfraim, L. A., Nguyen, A. P., Holdren, M. S., Campbell, J. S., Knight, B., Yeoh, G. C., Fausto, N., & Parks, W. T. (2006) · Hepatology · doi:10.1002/hep.21466 · Cited by 141 · see citing works
Leedham, S. J., Brittan, M., McDonald, S. A. C., & Wright, N. A. (2005) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2005.tb00333.x · Cited by 120 · see citing works
Alison, M. R., Golding, M., Lalani, E., Nagy, P., Thorgeirsson, S. S., & Sarraf, C. (1997) · Journal of Hepatology · doi:10.1016/s0168-8278(97)80051-7 · Cited by 119 · see citing works
Self-citationThe sources of parenchymal regeneration after chronic hepatocellular liver injury in mice
Vig, P., Russo, F. P., Edwards, R. J., Tadrous, P. J., Wright, N. A., Thomas, H. C., Alison, M. R., & Forbes, S. J. (2006) · Hepatology · doi:10.1002/hep.21018 · Cited by 118 · see citing works
Self-citationPaku, S., Nagy, P., Kopper, L., & Thorgeirsson, S. S. (2004) · Hepatology · doi:10.1002/hep.20178 · Cited by 117 · see citing works
VEGF is Important for Early Liver Regeneration After Partial Hepatectomy
Bockhorn, M., Góralski, M., Prokofiev, D. A., Dammann, P. R., Grünewald, P., Trippler, M., Biglarnia, A., Kamler, M., Niehues, E., Frilling, A., et al. (2007) · Journal of Surgical Research · doi:10.1016/j.jss.2006.07.027 · Cited by 116 · see citing works
Wilson, J. W., Groat, C. S., & Leduc, E. H. (1963) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1963.tb36945.x · Cited by 110 · see citing works
Transforming Growth Factor β1–Regulated Gene Expression of Ito Cells
Knittel, T. E., Janneck, T., Müller, L. P., Fellmer, P., & Ramadori, G. P. (1996) · Hepatology · doi:10.1002/hep.510240211 · Cited by 110 · see citing works
Terada, T., & Nakanuma, Y. (1994) · Histopathology · doi:10.1111/j.1365-2559.1994.tb01570.x · Cited by 98 · see citing works
Nylander, K., Bourdon, J., Bray, S. E., Gibbs, N. K., Kay, R. A., Hart, I. R., & Hall, P. A. (2000) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(200001)190:1 · Cited by 96 · see citing works
Knight, B., Akhurst, B., Matthews, V. B., Ruddell, R. G., Ramm, G. A., Abraham, L. J., Olynyk, J. K., & Yeoh, G. C. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.08.015 · Cited by 76 · see citing works
The isolation and in vitro expansion of hepatic Sca-1 progenitor cells
Clayton, E., & Forbes, S. J. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.02.079 · Cited by 26 · see citing works
Self-citationTransforming growth factor β1-regulated gene expression of Ito cells
Knittel, T. E. (1996) · Hepatology · doi:10.1053/jhep.1996.v24.pm0008690404 · Cited by 18 · see citing works
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Boulter, L., Govaere, O., Bird, T. G., Radulescu, S., Ramachandran, P., Pellicoro, A., Ridgway, R. A., Seo, S. S., Spee, B., Van Rooijen, N., et al. (2012) · Nature Medicine · doi:10.1038/nm.2667 · Cited by 747 · see citing works
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Lu, W.-Y., Bird, T. G., Boulter, L., Tsuchiya, A., Cole, A. M., Hay, T., Guest, R. V., Wojtacha, D., Man, T. Y., Mackinnon, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3203 · Cited by 479 · see citing works
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Gadd, V. L., Skoien, R., Powell, E. E., Fagan, K. J., Winterford, C., Horsfall, L., Irvine, K., & Clouston, A. D. (2014) · Hepatology · doi:10.1002/hep.26937 · Cited by 452 · see citing works
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Sato, K., Marzioni, M., Meng, F., Francis, H., Glaser, S., & Alpini, G. (2019) · Hepatology · doi:10.1002/hep.30150 · Cited by 423 · see citing works
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Español–Suñer, R., Carpentier, R., Van Hul, N., Legry, V., Achouri, Y., Cordi, S., Jacquemin, P., Lemaigre, F., & Leclercq, I. A. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.08.024 · Cited by 356 · see citing works
Thomas, J. A., Pope, C., Wojtacha, D., Robson, A. J., Gordon-Walker, T. T., Hartland, S., Ramachandran, P., Van Deemter, M., Hume, D. A., Iredale, J. P., et al. (2011) · Hepatology · doi:10.1002/hep.24315 · Cited by 346 · see citing works
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Campana, L., Esser, H., Huch, M., & Forbes, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00373-7 · Cited by 307 · see citing works
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Bird, T. G., Lu, W.-Y., Boulter, L., Gordon-Keylock, S., Ridgway, R. A., Williams, M. J., Taube, J., Thomas, J. A., Wojtacha, D., Gambardella, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1302168110 · Cited by 166 · see citing works
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The diversity and plasticity of adult hepatic progenitor cells and their niche
Chen, J., Chen, L., Zern, M. A., Theise, N. D., Diehl, A. M., Liu, P., & Duan, Y. (2017) · Liver International · doi:10.1111/liv.13377 · Cited by 51 · see citing works
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Banales, J. M., Marin, J. J. G., Lamarca, A., Rodrigues, P. M., Khan, S. A., Roberts, L. R., Cardinale, V., Carpino, G., Andersen, J. B., Braconi, C., et al. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0310-z · Cited by 2,411 · see citing works
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- Authors
- Lorenzini, S., Bird, T. G., Boulter, L., Bellamy, C., Samuel, K., Aucott, R., Clayton, E., Andreone, P., Bernardi, M., Golding, M., Alison, M. R., Iredale, J. P., & Forbes, S. J.
- Affiliations
- Centre for Inflammation Research (GB)
- MRC Centre for Regenerative Medicine (GB)
- Edinburgh Royal Infirmary (GB)
- University of Bologna (IT)
- Cancer Research UK (GB)
- Queen Mary University of London (GB)
- Corresponding author
- Forbes, Stuart J
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2010-04-28
- Volume
- 59
- Issue
- 5
- Pages
- 645-654
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC3034133
- OpenAlex
- W2122046893
- Cited by
- 190
- References
- 32
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 6 · 2023: 5 · 2022: 11 · 2021: 8 · 2020: 16 · 2019: 11 · 2018: 15 · 2017: 17 · 2016: 10 · 2015: 16 · 2014: 14 · 2013: 17 · 2012: 12
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (081604)
- European Association for the Study of the Liver
- Medical Research Council
- 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
- hepatic progenitor cells, laminin, liver injury, myofibroblasts, macrophages, bone marrow-derived cells, progenitor cell differentiation, tissue repair, extracellular matrix, hepatocyte differentiation
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Extracellular Matrix, Female, Humans, Laminin, Liver, Liver Diseases, Liver Regeneration, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Rats, Inbred F344, Recurrence, Stem Cells, Hepatitis C, Chronic, Hepatocytes, Endothelial Cells, Mice, Rats, Myofibroblasts
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