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Abstract
Cells with slow proliferation kinetics that retain the nuclear label over long time periods–the label-retaining cells (LRCs)–represent multipotent stem cells in a number of adult tissues. Since the identity of liver LRCs (LLRCs) had remained elusive we utilized a genetic approach to reveal LLRCs in normal non-injured livers and characterized their regenerative properties in vivo and in culture. We found that LLRCs were located in biliary vessels and participated in the regeneration of biliary but not hepatocyte injury. In culture experiments the sorted LLRCs displayed an enhanced self-renewal capacity but a unipotent biliary differentiation potential. Transcriptome analysis revealed a unique set of tumorigenesis- and nervous system-related genes upregulated in LLRCs when compared to non-LRC cholangiocytes. We conclude that the LLRCs established during the normal morphogenesis of the liver do not represent a multipotent primitive somatic stem cell population but act as unipotent biliary progenitor cells.
Highlights
In any of the six different liver injury models tested, demonstrating that liver biliary cells do not participate in hepatocyte regeneration
Our initial finding that the liver LRCs (LLRCs) were confined to cholangiocyte compartment was well in accord with a previous study that demonstrated the presence of LLRCs in portal regions of mouse liver[26]
Further functional evaluation of LLRCs revealed that these cells were induced to proliferate when bile duct injury was present and lineage-tracing experiments excluded any contribution from cholangiocytes towards hepatocyte compartment in 6 different well-characterized liver damage models. These observations corroborate the recently published studies, which showed that new hepatocytes arising during homeostatic liver maintenance or after liver injury were derived from pre-existing hepatocytes and did not originate from cholangiocytes or mesenchymal cells[4,5]
Summary
In any of the six different liver injury models tested, demonstrating that liver biliary cells do not participate in hepatocyte regeneration. In order to study the LLRC activation in response to bile duct injury, mice were either fed with DDC-supplemented chow for 4 weeks, administered CDE-diet for 3 weeks or subjected to tBDL and the liver was examined 3 weeks after surgery.
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