Spatiotemporal characterization of the cellular and molecular contributors to liver fibrosis in a murine hepatotoxic-injury model

Melino, Michelle, Gadd, Victoria L., Alexander, Kylie A., Beattie, Lynette, Lineburg, Katie E., Martinez, Michelle, Teal, Bianca, Le Texier, Laetitia, Irvine, Katharine M., Miller, Gregory C., Boyle, Glen M., Hill, Geoffrey R., Clouston, Andrew D., Powel, Elizabeth E. and MacDonald, Kelli P. A. (2016) Spatiotemporal characterization of the cellular and molecular contributors to liver fibrosis in a murine hepatotoxic-injury model. American Journal of Pathology, 186 3: 524-538. doi:10.1016/j.ajpath.2015.10.029


Author Melino, Michelle
Gadd, Victoria L.
Alexander, Kylie A.
Beattie, Lynette
Lineburg, Katie E.
Martinez, Michelle
Teal, Bianca
Le Texier, Laetitia
Irvine, Katharine M.
Miller, Gregory C.
Boyle, Glen M.
Hill, Geoffrey R.
Clouston, Andrew D.
Powel, Elizabeth E.
MacDonald, Kelli P. A.
Title Spatiotemporal characterization of the cellular and molecular contributors to liver fibrosis in a murine hepatotoxic-injury model
Journal name American Journal of Pathology   Check publisher's open access policy
ISSN 1525-2191
0002-9440
Publication date 2016-03-01
Sub-type Article (original research)
DOI 10.1016/j.ajpath.2015.10.029
Open Access Status Not yet assessed
Volume 186
Issue 3
Start page 524
End page 538
Total pages 15
Place of publication New York, United States
Publisher Elsevier
Collection year 2017
Language eng
Formatted abstract
The interplay between the inflammatory infiltrate and tissue resident cell populations invokes fibrogenesis. However, the temporal and mechanistic contributions of these cells to fibrosis are obscure. To address this issue, liver inflammation, ductular reaction (DR), and fibrosis were induced in C57BL/6 mice by thioacetamide administration for up to 12 weeks. Thioacetamide treatment induced two phases of liver fibrosis. A rapid pericentral inflammatory infiltrate enriched in F4/80+ monocytes co-localized with SMA+ myofibroblasts resulted in early collagen deposition, marking the start of an initial fibrotic phase (1 to 6 weeks). An expansion of bone marrow-derived macrophages preceded a second phase, characterized by accelerated progression of fibrosis (>6 weeks) after DR migration from the portal tracts to the centrilobular site of injury, in association with an increase in DR/macrophage interactions. Although chemokine (C-C motif) ligand 2 (CCL2) mRNA was induced rapidly in response to thioacetamide, CCL2 deficiency only partially abrogated fibrosis. In contrast, colony-stimulating factor 1 receptor blockade diminished C-C chemokine receptor type 2 [CCR2neg (Ly6Clo)] monocytes, attenuated the DR, and significantly reduced fibrosis, illustrating the critical role of colony-stimulating factor 1-dependent monocyte/macrophage differentiation and linking the two phases of injury. In response to liver injury, colony-stimulating factor 1 drives early monocyte-mediated myofibroblast activation and collagen deposition, subsequent macrophage differentiation, and their association with the advancing DR, the formation of fibrotic septa, and the progression of liver fibrosis to cirrhosis.
Keyword Fibrogenesis
Thioacetamide
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Fri, 07 Oct 2016, 21:39:34 EST by Anthony Yeates on behalf of Learning and Research Services (UQ Library)