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

Abstract

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.

Dynamic three‐dimensional morphogenesis of intrahepatic bile ducts in mouse liver development

“…Also, the techniques used in this study could become powerful tools for 3D structural analyses of the biliary network regeneration after liver injury in the field of regenerative medicine. Furthermore, because it has been suggested that gradients of hormonal factors and ECM components are involved in BD development during the processes of liver development and regeneration, the approaches in this study could be used to investigate the 3D gradients of hormonal factors and ECM components in microenvironments of the liver. As described above, the principal axis of the analyses with 3D structural reconstitution would be useful for developmental biology, pathology, and regenerative medicine.…”

Impact of suppression of tumorigenicity 14 (ST14)/serine protease 14 (Prss14) expression analysis on the prognosis and management of estrogen receptor negative breast cancer

“…Genes in the downstream pathway of ST14 were taken from previous publications [15, 19, 21, 24, 31, 68–78]. All gene sets were divided by the standard deviation of each gene after mean centering genes for gene normalization, using software Genesis (http://genome.tugraz.at).…”

Relationship between hepatic progenitor cell‐mediated liver regeneration and non‐parenchymal cells

“…As described above, HSCs surrounding HPC acting niche cells are also activated by TWEAK and are stimulated to secrete extracellular matrix (ECM) and several growth factors or ligands that are thought to play pivotal roles in maintaining HPC niche activation. [28][29][30][31] For example, hepatocyte growth factor (HGF), fibroblast growth factor 7 (FGF7), JAGGED1, TGF-β, and several epidermal growth factor receptor (EGFR) ligands, including EGF, TGF-α, and heparin-binding EGF, are recognized as potent effectors on HPC biology, and several experiments have been undertaken to evaluate the impact of these factors on HPC-mediated liver regeneration. 1,3 Among them, HGF and FGF7 are thought to play central roles in HPC biology because knockout of these molecules, but not others, in rodent liver disease models results in the failure of HPCmediated liver regeneration and ultimately leads to death due to hepatic failure.…”