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Am J Physiol Gastrointest Liver Physiol. 2016 Jan 1;310(1):G1-12. doi: 10.1152/ajpgi.00344.2015. Epub 2015 Nov 12.

Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver.

Author information

1
Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
2
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany;
3
Department of Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Saarland, Germany.
4
Insitute of Anatomy and Cell Biology, University of Saarland, Saarland, Germany; and.
5
Department of Medicine II, Saarland University Medical Center, Homburg, Germany; lukacsver@aol.com.

Abstract

Podoplanin/gp38(+) stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38(+) cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38(+) cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38(+) cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38(+) cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45(-)CD31(-)Asgpr1(-) liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38(hi)CD133(-), gp38(low)CD133(-), and gp38(-)CD133(-)). Moreover, among the CD133(+) cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38(-)CD133(+) and CD133(+)gp38(+)). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38(+)CD133(+) cells exhibited liver progenitor cell characteristics similar to the gp38(-)CD133(+) population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.

KEYWORDS:

NASH; fibrosis; inflammation; oval cells

PMID:
26564718
PMCID:
PMC4698439
DOI:
10.1152/ajpgi.00344.2015
[Indexed for MEDLINE]
Free PMC Article

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