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.
Highlights
Tissue repair in the adult mammalian liver occurs in two distinct processes, referred to as the first and second tiers of defense
When hepatocytic division is compromised, proliferation of epithelial cells in the canal of Hering, the most distal part of the biliary tree, is observed. Because of their ability to proliferate extensively, express proteins such as α-fetoprotein (Afp) and Delta-like 1 homolog (Dlk1), which are normally only found in hepatoblasts and hepatocytes during liver development, and to differentiate into fully functional hepatocytes or cholangiocytes, these cells are regarded as proliferating hepatic progenitor cells (HPCs) and constitute the second tier of defense in the reaction to injury
We opted to study the changes in expression patterns in a second tier of defense, represented by the 2-acetylaminofluorene combined with 70% partial hepatectomy (AAF/70% partial hepatectomy (PHx)) protocol, and compare the changes to those observed in a first tier of defense, represented by the PHx protocol
Summary
Tissue repair in the adult mammalian liver occurs in two distinct processes, referred to as the first and second tiers of defense. The adult liver possesses an exceptional regenerative capacity in response to injury, which can be accomplished through two distinct processes, referred to as the first and second tiers of defense. When hepatocytic division is compromised, proliferation of epithelial cells in the canal of Hering, the most distal part of the biliary tree, is observed. Because of their ability to proliferate extensively, express proteins such as α-fetoprotein (Afp) and Delta-like 1 homolog (Dlk1), which are normally only found in hepatoblasts and hepatocytes during liver development, and to differentiate into fully functional hepatocytes or cholangiocytes, these cells are regarded as proliferating hepatic progenitor cells (HPCs) and constitute the second tier of defense in the reaction to injury. The canal of Hering is, thought to comprise the adult hepatic progenitor cell niche, a protective microenvironment that serves to maintain and regulate HPC activity [2,3,4,5,6]
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