Expression of matrix metalloproteinase-2 and -9 and of tissue inhibitor of matrix metalloproteinase-1 in liver regeneration from oval cells in rat

Van, T. Pham; Couchie, Dominique; Martin–Garcia, Nadine; Laperche, Yannick; Zafrani, Elie‐Serge; Mavier, Philippe

doi:10.1016/j.matbio.2008.07.002

Cited by 19 publications

(11 citation statements)

References 33 publications

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“…Studies on the AAF/PHx protocol have shown that levels of matrix metalloproteinases (MMP) 2 and 9, which digest laminin and collagen IV, are increased in the HPC response [13]. In this study, our transcriptional profiling showed decreasing ( Mmp2 ) or almost constant ( Mmp9 ) levels over the period investigated (see Table 1 and panel h in Additional file 2).…”

Section: Resultssupporting

confidence: 49%

“…Previous studies support the proposition of an important role for the ECM in establishing specific hepatic microenvironments or niches to modulate the response of HPCs to tissue injury [6,13,15,29]. However, a detailed scheme of the molecules involved in remodeling of the ECM when the hepatic progenitor cell niche responds to liver injury has not yet been established.…”

Section: Discussionmentioning

confidence: 99%

“…A number of molecules involved in modulating this response have been identified [9]. Interestingly, they include several important players in ECM remodeling in liver fibrosis, such as connective tissue growth factor [10,11], transforming growth factor-β [12], which is active in ECM deposition, and matrix metalloproteinases 2, 9, and 12 (MMP-2, MMP-9 and MMP-12) and their inhibitor, tissue inhibitor of metalloproteinase type 1 (TIMP-1), which is involved in altered matrix degradation [13,14]. Furthermore, activation of ECM-producing cells and ECM deposition are reported to occur as an initial phase prior to HPC expansion in the injured liver, and in front of HPCs along the porto-veinous gradient of lobular invasion [15].…”

Section: Introductionmentioning

confidence: 99%

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Molecular constituents of the extracellular matrix in rat liver mounting a hepatic progenitor cell response for tissue repair

Vestentoft

Jelnes

Andersen

et al. 2013

Fibrogenesis Tissue Repair

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BackgroundTissue repair in the adult mammalian liver occurs in two distinct processes, referred to as the first and second tiers of defense. We undertook to characterize the changes in molecular constituents of the extracellular matrix when hepatic progenitor cells (HPCs) respond in a second tier of defense to liver injury.ResultsWe used transcriptional profiling on rat livers responding by a first tier (surgical removal of 70% of the liver mass (PHx protocol)) and a second tier (70% hepatectomy combined with exposure to 2-acetylaminofluorene (AAF/PHx protocol)) of defense to liver injury and compared the transcriptional signatures in untreated rat liver (control) with those from livers of day 1, day 5 and day 9 post hepatectomy in both protocols. Numerous transcripts encoding specific subunits of collagens, laminins, integrins, and various other extracellular matrix structural components were differentially up- or down-modulated (P < 0.01). The levels of a number of transcripts were significantly up-modulated, mainly in the second tier of defense (Agrn, Bgn, Fbn1, Col4a1, Col8a1, Col9a3, Lama5, Lamb1, Lamb2, Itga4, Igtb2, Itgb4, Itgb6, Nid2), and their signal intensities showed a strong or very strong correlation with Krt1-19, a well-established marker of a ductular/HPC reaction. Furthermore, a significant up-modulation and very strong correlation between the transcriptional profiles of Krt1-19 and St14 encoding matriptase, a component of a novel protease system, was found in the second tier of defense. Real-time PCR confirmed the modulation of St14 transcript levels and strong correlation to Krt-19 and also showed a significant up-modulation and strong correlation to Spint1 encoding HAI-1, a cognate inhibitor of matriptase. Immunodetection and three-dimensional reconstructions showed that laminin, Collagen1a1, agrin and nidogen1 surrounded bile ducts, proliferating cholangiocytes, and HPCs in ductular reactions regardless of the nature of defense. Similarly, matriptase and HAI-1 were expressed in cholangiocytes regardless of the tier of defense, but in the second tier of defense, a subpopulation of HPCs in ductular reactions co-expressed HAI-1 and the fetal hepatocyte marker Dlk1.ConclusionTranscriptional profiling and immunodetection, including three-dimensional reconstruction, generated a detailed overview of the extracellular matrix constituents expressed in a second tier of defense to liver injury.

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Section: Resultssupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular constituents of the extracellular matrix in rat liver mounting a hepatic progenitor cell response for tissue repair

Vestentoft

Jelnes

Andersen

et al. 2013

Fibrogenesis Tissue Repair

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“…Chronic liver injury leads to activation of oval cells after hepatocytes have exhausted their proliferative capacity (Conigliaro et al, 2010), and might contribute to the observed increase in Mmp2 and Mmp9 expression as shown in Fig. 3G (Pham Van et al, 2008). We examined the oval cell compartment by immunofluorescence labeling for the specific marker, A6 (Engelhardt et al, 1993).…”

Section: Resultsmentioning

confidence: 94%

Loss of lysosomal protein NCU-G1 results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells

Kong

Nesset

Damme

et al. 2014

Disease Models &Amp; Mechanisms

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Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.

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“…The role of macrophages in matrix degradation after CCl 4 injury is well described,23 and scar-associated macrophages produce MMP13, the predominant rodent collagenase, after CCl 4 injury 40. Work in the 2-acetylaminofluorene/partial hepatectomy rat model has shown that tissue inhibitor of metalloproteinase type 1 is expressed early, whereas MMP2 and MMP9, which digest basement membrane laminin and collagen IV, are upregulated later 55. The authors conclude that control of ECM laminin, via a temporal regulation of tissue inhibitor of metalloproteinase and MMP expression, enables the initial proliferation and subsequent differentiation of the HPC response.…”

Section: Discussionmentioning

confidence: 99%

Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response

Kallis

Robson

Fallowfield

et al. 2010

Gut

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Expression of matrix metalloproteinase-2 and -9 and of tissue inhibitor of matrix metalloproteinase-1 in liver regeneration from oval cells in rat

Cited by 19 publications

References 33 publications

Molecular constituents of the extracellular matrix in rat liver mounting a hepatic progenitor cell response for tissue repair

Molecular constituents of the extracellular matrix in rat liver mounting a hepatic progenitor cell response for tissue repair

Loss of lysosomal protein NCU-G1 results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells

Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response

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