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Immunohistochemical Characterization of Hepatic Progenitor Cell Niche in Liver Fibrosis of Elderly Cadavers
Author(s) -
Mak Ki Mark,
Chiu Sophia
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.740.7
Subject(s) - lobules of liver , pathology , hepatic stellate cell , extracellular matrix , laminin , myofibroblast , biology , cytokeratin , fibrosis , basement membrane , parenchyma , liver cytology , progenitor cell , immunostaining , hepatic fibrosis , immunohistochemistry , anatomy , microbiology and biotechnology , stem cell , medicine , biochemistry , liver metabolism
Human hepatic progenitor cells (HPC) normally reside in a quiescent state in the canals of Hering (COH) located at the interface between the portal tract and periportal parenchyma of the liver lobule. In chronic liver injury, HPC become activated and differentiate into cholangiocytes and hepatocytes, contributing to hepatic regeneration. HPC activation, termed ductular reaction or hepatic response, is accompanied by development of a HPC niche composed principally of laminin matrix, myofibroblasts and macrophages. The composition of the niche is likely to be a determinant of HPC behavior. Preliminary studies found activation of HPC in the periportal parenchyma and occurrence of HPC deep in the liver lobule of elderly cadavers with progressive stages of liver fibrosis (FASEB 2006; 30:1044.4; 1044.5). The present study assessed the composition of the niche proteins and fibrogenic cells in liver fibrosis of elderly cadavers by immunohistochemistry. HPC are ~ 8 μm in size showing an oval to cuboidal morphology with scant cytoplasm and express cytokeratin 7 (CK7), CK19 or epithelial cell adhesion molecule. Immunostaining showed that the COH were marked by a basement membrane positive for collagen IV and laminin. The niche surrounding the COH contained a rich collagenous matrix, revealed by Sirius red stain for collagens. Moreover, the matrix displayed an array of fibrillar collagen I, III and V and filamentous collagen VI. Hepatic stellate cells/myofibroblasts labeled by a‐smooth muscle actin were present in the collagenous matrix surrounding the COH. In the periportal parenchyma where ductular reaction occurred in response to fibrogenesis, reactive ductules composed of strings of HPC were marked by collagen IV and laminin and surrounded by a collagenous matrix containing collagen fibers and fibrogenic cells. Similarly, collagens and fibrogenic cells were observed in the matrix associated with isolated HPC in the deeper part of the lobule, as well as in the HPC‐containing ductules in the developing fibrous septa and bridging septa. Conclusions/implications The HPC niche contains collagen IV and laminin that provide a basement membrane supporting the COH and HPC. The laminin matrix supports HPC in an undifferentiated phenotype and suppresses hepatocye differentiation. The collagen fibers confer strength on the matrix scaffolds of the HPC niche. Moreover, while collagen V regulates fibrillogenesis of collagen I, collagen VI, a connecting protein, links fibrillar collagens to the niche matrix. Collagen V and VI also bind cytokines, growth factors and matrix metalloproteinases, regulating their availability to HPC. Hepatic stellate cells/myofibroblasts contribute to remodeling of the HPC niche matrix. The composition of the niche matrix likely influences the HPC fate in the aged liver.