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Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells
Open accessAbstract
Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor–like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin–positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFκB subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFκB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (Hepatology 2010)
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“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 [33]
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“HPCs had a corresponding reduction in NFκB activity (Figure 5g), a downstream mediator of TWEAK-Fn14 signalling33.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [33]
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“A study has shown that CDE diet induces elevated Fn14 expression in the liver and Fn14 is colocalized with panCK.(68) This study has also demonstrated that Fn14 knockout mice show less DR (A6+ or CK19+ cell counts) during CDE diet compared with wildtype, and treatments of TWEAK, which is an Fn14 ligand, induce prolife…”
BackgroundThomas, 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
“Interestingly, endogenous hepatic macrophages have recently been identified as a cellular source of TWEAK during chronic liver injury.(31) Donor BMMs used in our studies expressed high levels of TWEAK and recruited additional host macrophages to the injured liver, supporting the paradigm of donor cell-derived paracrin…”
BackgroundNovel insights into the function and dynamics of extracellular matrix in liver fibrosis
Karsdal, M. A., Manon‐Jensen, T., Genovese, F., Kristensen, J. H., Nielsen, M. J., Sand, J. M. B., Hansen, N. U. B., Bay‐Jensen, A., Bager, C. L., Krag, A. A., et al. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00447.2014 · Cited by 265
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“Further insights supporting our model that the immune system is a source of TWEAK that regulates tissue regeneration responses have been gleaned from studies in another model of liver injury and oval cell expansion induced by choline-deficient ethionine (CDE)-supplemented diet (69).”
BackgroundInfluentialAffò, S., Domínguez, M., Lozano, J. J., Sancho‐Bru, P., Rodrigo‐Torres, D., Morales‐Ibanez, O., Moreno, M., Millán, C., Loaeza-del-Castillo, A., Altamirano, J., et al. (2012) · Gut · doi:10.1136/gutjnl-2011-301146 · Cited by 211
Ishikawa, T., Factor, V. M., Marquardt, J. U., Raggi, C., Seo, D., Kitade, M., Conner, E. A., & Thorgeirsson, S. S. (2011) · Hepatology · doi:10.1002/hep.24796 · Cited by 189
Effects of inflammation on stem cells: together they strive?
Kızıl, Ç., Kyritsis, N., & Brand, M. (2015) · EMBO Reports · doi:10.15252/embr.201439702 · Cited by 190
“Macrophages and inflammatory response are potent determinants of liver progenitor cell (LPC) expansion [101].”
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
“We now show that exogenous TWEAK administration results in DR expansion in vivo and in addition confirm TWEAK expression by hepatic macrophages and Fn14 expression by panCK DRs, which have been shown to mediate ductular proliferation via NFκB activation (16, 17).”
BackgroundFeng, D., Kong, X., Weng, H., Park, O., Wang, H., Dooley, S., Gershwin, M. E., & Gao, B. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.03.044 · Cited by 167
Cell therapy for advanced liver diseases: repair or rebuild
Dwyer, B. J., Macmillan, M. T., Brennan, P. N., & Forbes, S. J. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.09.014 · Cited by 141
Alcoholic Hepatitis: Current Challenges and Future Directions
Singal, A. K., Kamath, P. S., Gores, G. J., & Shah, V. H. (2013) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2013.06.013 · Cited by 153
Liver regeneration by stem/progenitor cells
Itoh, T., & Miyajima, A. (2013) · Hepatology · doi:10.1002/hep.26753 · Cited by 155
“Conversely, in mice lacking the TWEAK receptor, Fn14, as well as in those treated with a neutralizing anti-TWEAK mAb, LPC response upon the DDC or CDE regimen was significantly suppressed.(77,78) However, this suppression was only in a partial or transient manner, implicating a role of some other signals for LPC activ…”
BackgroundTakase, H. M., Itoh, T., Ino, S., Wang, T., Koji, T., Akira, S., Takikawa, Y., & Miyajima, A. (2013) · Genes & Development · doi:10.1101/gad.204776.112 · Cited by 143
“Previous studies have identified TNF (tumor necrosis factor)-like weak inducer of apoptosis (Tweak) as a mitogen for LPCs (Jakubowski et al. 2005; Tirnitz-Parker et al. 2010).”
BackgroundResultLiver stem/progenitor cells: their characteristics and regulatory mechanisms
Tanaka, M., Itoh, T., Tanimizu, N., & Miyajima, A. (2011) · The Journal of Biochemistry · doi:10.1093/jb/mvr001 · Cited by 138
Understanding the marvels behind liver regeneration
Rmilah, A. A. A., Zhou, W., Nelson, E., Li, L., Amiot, B. P., & Nyberg, S. L. (2019) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.340 · Cited by 133
“E. Tirnitz-Parker et al. (2010) have published that TWEAK injection in unharmed mouse liver can result in a robust expansion of HPSCs.”
BackgroundEpithelial Plasticity during Liver Injury and Regeneration
Gadd, V. L., Aleksieva, N., & Forbes, S. J. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.08.016 · Cited by 142
Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development
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“However, under pathological conditions, Fn14 expression is rapidly induced in several tissues such as liver [116], heart [117], colon [118], skeletal muscle [119], as well as during atherosclerosis [120] and kidney injury [121].”
BackgroundTWEAK, a multifunctional cytokine in kidney injury
Sanz, A. B., Sánchez-Niño, M. D., & Ortíz, A. (2011) · Kidney International · doi:10.1038/ki.2011.180 · Cited by 123
Role of TWEAK in lupus nephritis: A bench-to-bedside review
Michaelson, J. S., Wisniacki, N., Burkly, L. C., & Putterman, C. (2012) · Journal of Autoimmunity · doi:10.1016/j.jaut.2012.05.003 · Cited by 117
“Fn14 expression has been shown to be elevated locally in the tissues of experimental models of injury and inflammation, such as the injured heart [38], vasculature [39, 40], skeletal muscle [41] or denervation [42], intestinal epithelium [37], spinal cord [43-45] and liver [46, 47].”
BackgroundDifferentiation of progenitors in the liver: a matter of local choice
Boulter, L., Lu, W.-Y., & Forbes, S. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66026 · Cited by 116
“What is known is that this putative stem cell gives rise to a transit-amplifying population of HPCs. Mechanisms of HPCs have been increasingly studied, and a broad class of factors that can activate the proliferation of HPCs has been identified (16, 17).”
Liver 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 117
TWEAK and the progression of renal disease: clinical translation
Sanz, A. B., Izquierdo, M. C., Sánchez-Niño, M. D., Ucero, A. C., Egido, J., Ruiz‐Ortega, M., Ramos, A. M., Putterman, C., & Ortíz, A. (2014) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft342 · Cited by 111
Kuramitsu, K., Sverdlov, D., Liu, S. B., Csizmadia, E., Burkly, L. C., Schuppan, D., Hanto, D. W., Otterbein, L. E., & Popov, Y. V. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.03.018 · Cited by 109
“Although we cannot entirely rule out that TWEAK may act on several cell types in the liver, the most pronounced (and reported in vivo) effect of overexpression or exogenous administration of TWEAK is oval cell and progenitor proliferation.(25,26) In summary, we have established a sequence of pathological events associ…”
BackgroundMethodUcero, A. C., Benito‐Martín, A., Calvo, I. F., Santamaría, B., Blanco, J., López-Novoa, J. M., Ruiz‐Ortega, M., Egido, J., Burkly, L. C., Martínez‐Salgado, C., et al. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.032 · Cited by 101
“TWEAK regulates some ECM-related proteins, namely matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) in other organ systems [17, 23-26] but there is no information on the role of TWEAK and its receptor in renal fibroblasts.”
BackgroundBurkly, L. C. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.02.006 · Cited by 90
Guillot, A., Guerri, L., Feng, D., Kim, S.-J., Ahmed, Y. A., Paloczi, J., He, Y., Schuebel, K., Dai, S., Liu, F., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci132305 · Cited by 86
“Indeed, our data showed that liver macrophages isolated at the peak of BEC proliferation overexpressed Tweak, a known mitogen for BECs and liver progenitor cells (29, 41, 42).”
BackgroundMethodTWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression
Dwyer, B. J., Jarman, E. J., Gogoi-Tiwari, J., Ferreira-González, S., Boulter, L., Guest, R. V., Kendall, T. J., Kurian, D., Kilpatrick, A. M., Robson, A. J., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.11.018 · Cited by 84
“Previous studies reported proliferation of biliary epithelial, and HCC cells, in response to TWEAK.21,22,25,32 We explored the effects of TWEAK in CCA lines and found that TWEAK modulated NF-jB signalling in all investigated CCA cell lines, but not HepG2 HCC cells.”
BackgroundResultInfluentialSelf-citationCancer stem cells and hepatocellular carcinoma
Yao, Z., & Mishra, L. (2009) · Cancer Biology & Therapy · doi:10.4161/cbt.8.18.9843 · Cited by 81
TWEAK/Fn14 Axis: A Promising Target for the Treatment of Cardiovascular Diseases
Blanco‐Colio, L. M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00003 · Cited by 80
“By contrast, Fn14 expression in healthy tissues, including the vasculature and heart, is usually low or undetectable, although it is rapidly and highly upregulated under pathological conditions as demonstrated in experimental models of chronic liver injury (14), myocardial infarction (15), colitis (16), denervation-in…”
BackgroundChua, A. C. G., Klopcic, B. R. S., Ho, D. S., Fu, S. K., Forrest, C. H., Croft, K. D., Olynyk, J. K., Lawrance, I. C., & Trinder, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078850 · Cited by 76
“Immunofluorescence was performed on cryosections of the colon fixed in 4% paraformaldehyde in phosphate-buffered saline as previously described.[21] Rabbit anti-ferritin (1:500, Dako), biotinylated rat anti-F4/80 (1:50, AbD Serotec, Raleigh, NC), rat anti-IL-6 (1:100, BD Biosciences, North Ryde, NSW, Australia) and ra…”
MethodSelf-citationTWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
Karaca, G., Swiderska‐Syn, M., Xie, G., Syn, W., Krüger, L., Machado, M. V., Garman, K. S., Choi, S. S., Michelotti, G. A., Burkly, L. C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0083987 · Cited by 71
“However, as others reported,[4,7] we found that recombinant TWEAK was unable to stimulate proliferation of primary hepatocytes isolated from the livers of healthy adult mice even at doses as high as 10 ng/ml (Figure S3B), or when used in conjunction with IL6, a putative hepatotrophic cytokine (data not shown).”
BackgroundMethodResultInfluentialWilhelm, A., Shepherd, E. L., Amatucci, A., Munir, M., Reynolds, G. M., Humphreys, E. H., Resheq, Y. J., Adams, D., Hübscher, S. G., Burkly, L. C., et al. (2016) · The Journal of Pathology · doi:10.1002/path.4707 · Cited by 70
“These results were similar to previously published data in mice on the CDE diet [9,14].”
BackgroundResultInfluentialHepatic 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 67
Enwere, E. K., LaCasse, E. C., Adam, N., & Korneluk, R. G. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00034 · Cited by 65
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“This was shown by the Fn14 dependence of collagen deposition and TIMP-1 and -2 expression in a liver injury model [73].”
BackgroundInfluentialThe role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis
Köhn‐Gaone, J., Gogoi-Tiwari, J., Ramm, G. A., Olynyk, J. K., & Tirnitz‐Parker, J. E. E. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00215.2015 · Cited by 58
Self-citationTWEAK/Fn14 axis is an important player in fibrosis
Zhang, Y., Zeng, W., & Xia, Y. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30089 · Cited by 57
Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice
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Delima, R. D., Chua, A. C. G., Tirnitz‐Parker, J. E. E., Gan, E. K., Croft, K. D., Graham, R. M., Olynyk, J. K., & Trinder, D. (2012) · Hepatology · doi:10.1002/hep.25689 · Cited by 55
“Liver sections were stained with Perls’ Prussian blue for the detection of tissue iron as well as with Sirius red and Masson’s trichrome for the detection of collagen.(26) Stained sections were digitized using an Aperio Scanscope XT (Aperio Technologies, Vista, CA) and analyzed using a positive pixel-count algorithm s…”
MethodSelf-citationThe 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
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Role of liver progenitors in acute liver injury
Best, J., Dollé, L., Manka, P. P., Coombes, J. D., van Grunsven, L. A., & Syn, W. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00258 · Cited by 50
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“Changes in Fn14 expression have been reported in experimental models of different pathologies, such as chronic liver injury [19], myocardial infarction [20], restenosis after balloon injury and femoral wire injury [11,21], atherosclerosis [18], acute kidney injury [22], or cardiac dysfunction [23], among others.”
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 49
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“TWEAK binds to its receptor Fn14 and upregulates NF-κB signalling then directly stimulates liver progenitor cells (LPCs) mitosis to mediate liver regeneration after liver injury (Tirnitz-Parker et al., 2010).”
The Origin, Biology, and Therapeutic Potential of Facultative Adult Hepatic Progenitor Cells
Shin, S., & Kaestner, K. H. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-416022-4.00010-x · Cited by 46
TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice
Son, A., Oshio, T., Kawamura, Y. I., Hagiwara, T., YAMAZAKI, M., Inagaki-Ohara, K., Okada, T., Wu, P., Iseki, M., Takaki, S., et al. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.10 · Cited by 44
“All experimental protocols were approved by the local institutional animal care and use committees of the National Center for Global Health and Medicine, Japan.”
BackgroundInfluentialTWEAK and LTβ Signaling during Chronic Liver Disease
Dwyer, B. J., Olynyk, J. K., Ramm, G. A., & Tirnitz‐Parker, J. E. E. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00039 · Cited by 41
“Conversely, ductal cell expansion is mitigated after pharmacological blocking of TWEAK signaling as well as in Fn14-knockout mice subjected to either 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or cholinedeficient, ethionine-supplemented (CDE)-induced chronic liver injury (22, 32).”
BackgroundInfluentialSelf-citationRelationship between hepatic progenitor cell‐mediated liver regeneration and non‐parenchymal cells
Kitade, M., Kaji, K., & Yoshiji, H. (2016) · Hepatology Research · doi:10.1111/hepr.12682 · Cited by 41
Role of liver progenitors in liver regeneration.
Best, J., Manka, P. P., Syn, W., Dollé, L., van Grunsven, L. A., & Canbay, A. E. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2304-3881.2015.01.16 · Cited by 44
“TWEAK then signals via the TWEAK receptor Fn14 and downstream NF-κB to induce LPC proliferation (34).”
BackgroundHou, X., Ye, F., Li, X., Liu, W., Jing, Y., Han, Z., & Wei, L. (2017) · Cellular Immunology · doi:10.1016/j.cellimm.2017.08.004 · Cited by 41
“Tirnitz-Parker[87] Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) Fn14 knockout (KO) mice TWEAK represents as a mitogen for liver progenitor cells”
BackgroundPathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles
Lim, H. K., Jeffrey, G. P., Ramm, G. A., & Soekmadji, C. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.587628 · Cited by 45
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Köhn‐Gaone, J., Dwyer, B. J., Grzelak, C. A., Miller, G. C., Shackel, N. A., Ramm, G. A., McCaughan, G. W., Elsegood, C. L., Olynyk, J. K., & Tirnitz‐Parker, J. E. E. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.03.005 · Cited by 38
Self-citationGuillot, A., Gasmi, I., Brouillet, A., Ait‐Ahmed, Y., Calderaro, J., Ruiz, I., Gao, B., Lotersztajn, S., Pawlotsky, J., & Lafdil, F. (2018) · Hepatology Communications · doi:10.1002/hep4.1145 · Cited by 38
“(IFN-c), interleukin-6 (IL-6), IL-22, and lymphotoxin b.((24-28)) Among the key players in modulating liver inflammation, T helper (Th)17 lymphocytes have been implicated in several types of liver diseases through the effects of IL-17A (IL-17) and IL-22.”
BackgroundCarlessi, R., Köhn‐Gaone, J., Olynyk, J. K., & Tirnitz‐Parker, J. E. E. (2019) · Codon Publications eBooks · doi:10.15586/hepatocellularcarcinoma.2019 · Cited by 39
Self-citationIron and Hepatic Carcinogenesis
Tirnitz‐Parker, J. E. E., Glanfield, A., Olynyk, J. K., & Ramm, G. A. (2013) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2013007759 · Cited by 42
Self-citationAlcoholic Hepatitis: Prognostic Models and Treatment
Singal, A. K., & Shah, V. H. (2011) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2011.06.008 · Cited by 37
Soeda, J., Mouralidarane, A., Ray, S., Novelli, M. R., THOMAS, S. A., Roskams, T., Diehl, A. M., & Oben, J. A. (2014) · Hepatology · doi:10.1002/hep.27266 · Cited by 37
“TWEAK has been reported to specifically promote progenitor cell expansion in liver and to have no effect on hepatocytes.(28,29) Therefore, we administered recombinant TWEAK before APAP treatment to force expansion of endogenous HPCs.”
Irvine, K. M., Clouston, A. D., Gadd, V. L., Miller, G. C., Wong, W.-Y., Melino, M., Maradana, M. R., MacDonald, K. P. A., Lang, R. A., Sweet, M. J., et al. (2015) · Fibrogenesis & Tissue Repair · doi:10.1186/s13069-015-0036-7 · Cited by 35
“Inflammatory cytokines (e.g. IL-6, TNF, LTβ, IFNγ) [20–23], injury-induced growth factors (e.g. TWEAK [24]) and extracellular matrix components (e.g. collagen, laminin and fibronectin [25, 26]) are also implicated in regulating HPC proliferation and fate.”
BackgroundInfluentialShort, C. A., Zhong, A. C., Xu, J., Mahdi, E. M., Glazier, A., Malkoff, N., Noriega, N., Yeo, T., Asahina, K., & Wang, K. S. (2023) · Hepatology · doi:10.1097/hep.0000000000000026 · Cited by 34
“These data indicate the mitogenic effect of rmTWEAK on murine HPC organoid proliferation and the direct effect of L5240366 on the inhibition of the TWEAK/FN14 pathway in HPC organoids expressing both PROM1 and FN14.”
BackgroundResultInfluentialBest, J., Verhulst, S., Syn, W., Lagaisse, K., Hul, N. V., Heindryckx, F., Sowa, J., Peeters, L., Vlierberghe, H. V., Leclercq, I. A., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162286 · Cited by 32
Wang, Y., Zhang, S., Xie, X., Chen, Z., Wu, L., Yu, Z., Guo, X., & Chen, G. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2019.01299 · Cited by 32
“TNFRSF12A is expressed in progenitor cells in response to liver injury (Jakubowski et al., 2005; Tirnitz-Parker et al., 2010).”
BackgroundProgress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases
Li, T., Ren, X., Zhai, W., & Chen, Z. (2022) · Molecules · doi:10.3390/molecules27134275 · Cited by 35
Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives
Katoonizadeh, A., Poustchi, H., & Malekzadeh, R. (2014) · Liver International · doi:10.1111/liv.12573 · Cited by 30
“Using recombinant TWEAK to stimulate oval cell expansion, a recent study claimed a progenitor (oval) cell-driven fibrogenic response in fibrotic mice undergoing PH (46).”
BackgroundRole of TWEAK in coregulating liver progenitor cell and fibrogenic responses
Tirnitz‐Parker, J. E. E., Olynyk, J. K., & Ramm, G. A. (2013) · Hepatology · doi:10.1002/hep.26701 · Cited by 29
“A previous study provides some evidence for a link between TWEAK-regulated LPC and fibrogenic responses by demonstrating that Fn14-deficient mice subjected to a choline-deficient, ethionine-supplemented (CDE) diet showed diminished LPC proliferation as well as reduced collagen deposition and transcript levels of tissu…”
BackgroundSelf-citationPrakoso, E., Tirnitz‐Parker, J. E. E., Clouston, A. D., Kayali, Z., Lee, A., Gan, E. K., Ramm, G. A., Kench, J. G., Bowen, D. G., Olynyk, J. K., et al. (2014) · Liver Transplantation · doi:10.1002/lt.24007 · Cited by 30
“However, the current study and previous studies indicate that hepatic inflammation occurring in HCV-associated liver injury, either before or after LT, appears to drive fibrosis and HPC proliferation and the DR.”
BackgroundResultInfluentialSelf-citationDuctular Reactions in Liver Injury, Regeneration, and Disease Progression—An Overview
Mavila, N., Eshwaraiah, M. S., & Kennedy, J. (2024) · Cells · doi:10.3390/cells13070579 · Cited by 33
Gurunathan, S., Winkles, J. A., Ghosh, S., & Hayden, M. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.563478 · Cited by 29
Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease
Sharif, M., Campanholle, G., Nagiec, E. E., Wang, J., Syed, J., O’Neil, S. P., Zhan, Y., Brenneman, K. A., Homer, B., Neubert, H., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0155368 · Cited by 29
Lam, E. T., Eckhardt, S., Messersmith, W. A., Jimeno, A., O’Bryant, C. L., Ramanathan, R. K., Weiss, G. J., Chadha, M. K., Oey, A., Ding, H. T., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0330 · Cited by 31
Xiao, M.-H., Ma, D., Wu, S., Huang, Z., Liang, P., Chen, H., Zhong, Z., Li, W., Wang, F., Tang, Y., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000001064 · Cited by 33
“[34,35] 38] These data demonstrate that the TNFSF12-TNFRSF12A pathway accelerates the ductular reaction by acting on multiple cell types.”
Chen, L., Luo, M., Sun, X., Qin, J., Yu, C., Wen, Y., Zhang, Q., Gu, J., Xia, Q., & Kong, X. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.161 · Cited by 25
“Tirnitz-Parker et al.(16) showed that these responses co-regulated the LPC proliferation in amurinemodel induced by CDE.”
BackgroundResultInfluentialMechanisms of ductular reaction in non-alcoholic steatohepatitis
Chen, Y., Gao, W.-K., Shu, Y.-Y., & Ye, J. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i19.2088 · Cited by 25
Müller, M., Wetzel, S., Köhn‐Gaone, J., Chalupský, K., Lüllmann‐Rauch, R., Barikbin, R., Bergmann, J., Wöhner, B., Zbodakova, O., Leuschner, I., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7836 · Cited by 25
“In accordance with previous reports [17] TWEAK (Tnfsf12) expression levels remained unchanged (Figure 4B).”
BackgroundResultInfluentialSelf-citationKramer, A. S., Latham, B. I., Diepeveen, L. A., Mou, L., Laurent, G. J., Elsegood, C. L., Ochoa‐Callejero, L., & Yeoh, G. C. (2018) · Scientific Reports · doi:10.1038/s41598-018-21757-4 · Cited by 24
Self-citationLiver progenitor cell interactions with the extracellular matrix
Zhu, C., Coombe, D. R., Zheng, M., Yeoh, G. C., & Li, L. (2012) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.1470 · Cited by 26
Self-citationLiu, W., Ren, L., Wang, T., Navarro–Álvarez, N., & Tang, L. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.15715 · Cited by 25
“One of the best-established cytokines among these is TWEAK, which is produced by macrophages and has great paracrine effect on LSPCs activation and expansion [59-62].”
BackgroundModulation of the Activity of Stem and Progenitor Cells by Immune Cells
Alshoubaki, Y. K., Nayer, B., Das, S., & Martino, M. M. (2022) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szab022 · Cited by 25
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and kidney disease
Ruiz‐Ortega, M., Ortíz, A., & Ramos, A. M. (2013) · Current Opinion in Nephrology & Hypertension · doi:10.1097/01.mnh.0000437331.23794.81 · Cited by 23
“In the liver, TWEAK induces progenitor cell proliferation in vivo [28].”
BackgroundAdvances in hepatic stem/progenitor cell biology
Verhulst, S., Best, J., van Grunsven, L. A., & Dollé, L. (2015) · PubMed Central · doi:10.17179/excli2014-576 · Cited by 23
“deficient mice was attenuated after CDE treatment, it was restored later on and ultimately resulted in a level similar to that in WT mice (Tirnitz-Parker et al., 2010).”
ResultMicroenvironmental control of the ductular reaction: balancing repair and disease progression
Sorrentino, G. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07590-4 · Cited by 26
Antibody-Targeted TNFRSF Activation for Cancer Immunotherapy: The Role of FcγRIIB Cross-Linking
Liu, L., Wu, Y. M., Ye, K., Cai, M., Zhuang, G., & Wang, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.924197 · Cited by 22
“…against tumor challenge Maecker et al. (2005) TNFRSF12A (Fn14, TWEAKR) Reduced proliferative capacity; altered myotube formation Girgenrath et al. (2006); Reduced LPC numbers; attenuated inflammation; cytokine production Tirnitz-Parker et al. (2010) primary antibody deficiency Wang et al. (2013)”
BackgroundRenal fibrosis in type 2 cardiorenal syndrome: An update on mechanisms and therapeutic opportunities
Xu, X., Zhang, B., Wang, Y., Shi, S., Lv, J., Fu, Z., Gao, X., Li, Y., Wu, H., & Song, Q. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114901 · Cited by 25
TWEAK regulates proliferation and differentiation of adult neural progenitor cells
Schölzke, M. N., Röttinger, A., Murikinati, S. R., Gehrig, N., Leib, C., & Schwaninger, M. (2010) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2010.10.004 · Cited by 22
Nrf2 Is Involved in Maintaining Hepatocyte Identity during Liver Regeneration
Zou, Y., Lee, J., Nambiar, S. M., Hu, M., Rui, W., Bao, Q., Chan, J. Y., & Dai, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107423 · Cited by 21
Lammens, A., Baehner, M., Kohnert, U., Niewoehner, J., von Proff, L., Schräml, M., Lammens, K., & Hopfner, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062697 · Cited by 22
“The large repertoire of cellular responses together with the broad range of cell types expressing TWEAK and Fn14 makes them key regulators of progenitor expansion, cell proliferation, cell migration, angiogenesis and inflammation during tissue repair after acute injuries and in physiological tissue remodeling [4,8,27–…”
BackgroundPassman, A. M., Strauss, R. P., McSpadden, S. B., Finch‐Edmondson, M., Andrewartha, N., Woo, K. H., Diepeveen, L. A., Zhao, W., Fernández‐Irigoyen, J., Santamaría, E., et al. (2021) · Cancers · doi:10.3390/cancers13194935 · Cited by 21
“The LPC response is also diminished in lymphotoxin beta KO mice [25] and Fn14 KO mice in which tumour necrosis factor-like weak inducer of apoptosis (TWEAK) signalling is attenuated and both inflammation and the LPC response are suppressed [26].”
BackgroundSelf-citationZhang, F., Zhang, M., Wang, A., Xu, M., Wang, C., Xu, G., Zhang, B., Zou, X., & Zhuge, Y. (2016) · Cell Biology International · doi:10.1002/cbin.10706 · Cited by 21
“For the following experiments, LX-2 was maintained with 100 ng/mL of TWEAK for 24 h, the concentration of which was referred to previous studies (Jakubowski et al., 2005; Tirnitz-Parker et al., 2010) and determined by our preliminary experiment.”
MethodResultMolecular Survey of Cell Source Usage during Subtotal Hepatectomy-Induced Liver Regeneration in Rats
Elchaninov, A. V., Fatkhudinov, T., Usman, N. Y., Kananykhina, E. Y., Arutyunyan, I. V., Макаров, А. В., Bolshakova, G. B., Goldshtein, D. V., & Sukhikh, G. T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162613 · Cited by 19
“TWEAK is a potent inducer of HPC proliferation [16,17,18]; in particular, it has a selectivemitogenic effect for the liver progenitor ("oval") cells in rodents, while an increased Fn14 expression in chronic hepatitis C and related diseases suggests a similar role for the TWEAK/Fn14 pathway in humans [19].”
BackgroundMorales-Garza, L. A., Puche, J. E., Aguirre, G. A., Muñoz, Ú., García‐Magariño, M., de la Garza, R. G., & Castilla‐Cortázar, I. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-017-1198-4 · Cited by 19
“On the other hand, TNF-α gene expression was significantly augmented in Wt + CCl4, showing a normal inflammatory response suggesting a better hepatic regeneration capability [22].”
BackgroundTWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes
Salzmann, S., Lang, I., Rosenthal, A., Schäfer, V., Weisenberger, D., Arana, J. A. C., Trebing, J., Siegmund, D., Neumann, M., & Wajant, H. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202899 · Cited by 20
“In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6, 7), regulation of muscle development and muscle regeneration (8–11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus…”
BackgroundRoles of Fibroblast Growth Factor-inducible 14 in Hepatocellular Carcinoma
Li, N., Hu, W., Shi, J., Xue, J., Guo, W., Zhang, Y., Guan, D., Liu, S., Cheng, Y., Wu, M.-C., et al. (2013) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2013.14.6.3509 · Cited by 19
“A recent investigation demonstrated, that the TWEAK/ Fn14 pathway can stimulate liver progenitor cell (LPC) mitosis in the rapid growth phase during response to choline-deficient, ethionine-supplemented (CDE) dietinduced injury and re-generation in vivo (Tirnitz-Parker et al., 2010).”
BackgroundHepatic progenitor cells in canine and feline medicine: potential for regenerative strategies
Kruitwagen, H. S., Spee, B., & Schotanus, B. A. (2014) · BMC Veterinary Research · doi:10.1186/1746-6148-10-137 · Cited by 19
“TWEAK) produced by this inflammatory cell can modulate HPC behavior over large distances in the tissue [77,78].”
Background
Metadata
- Authors
- Tirnitz-Parker, J. E. E., Viebahn, C. S., Jakubowski, A., Klopcic, B. R. S., Olynyk, J. K., Yeoh, G. C. T., & Knight, B.
- Affiliations
- The University of Western Australia (AU)
- Biogen (United States) (US)
- Centre for Inflammation Research (GB)
- Venue
- Hepatology
- Published
- 2010-07
- Volume
- 52
- Issue
- 1
- Pages
- 291-302
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2005176562
- Cited by
- 177
- References
- 53
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 7 · 2018: 6 · 2017: 18 · 2016: 18 · 2015: 15 · 2014: 18 · 2013: 20 · 2012: 16
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Funders
- University of Edinburgh
- Gastroenterological Society of Australia
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- TWEAK, Fn14, liver progenitor cells, chronic liver injury, liver regeneration, cell proliferation, NF-κB signaling, p50 subunit, hepatic stellate cells, liver fibrosis, choline-deficient ethionine-supplemented diet, cytokine production, inflammation
- MeSH terms
- Cytokine TWEAK, TWEAK Receptor, Animals, Choline Deficiency, Collagen, Ethionine, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Mitogens, Mitosis, Recombinant Proteins, Stem Cells, NF-kappa B, Receptors, Tumor Necrosis Factor, Mice, Knockout, Tumor Necrosis Factors, Cell Proliferation, Mice
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