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Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice.
- Source :
-
Journal of hepatology [J Hepatol] 2017 Oct; Vol. 67 (4), pp. 770-779. Date of Electronic Publication: 2017 Jul 26. - Publication Year :
- 2017
-
Abstract
- Background & Aims: Macrophages play vital roles in chronic liver injury, and have been tested as a tool for cytotherapy in liver fibrosis. However, macrophages possess ontogenic and functional heterogeneities. Some subsets are pro-fibrotic, whereas others are anti-fibrotic. This study aimed to clarify which macrophage subset is efficient for cytotherapy in liver fibrosis and to elucidate the underlying mechanisms.<br />Methods: Liver fibrosis was induced in mice by carbon tetrachloride injection or bile duct ligation. Bone-marrow-derived macrophages (BMDMs) were polarized into M0, M1, or M2 macrophages, respectively. BMDMs were infused into mice through the tail vein at different stages of fibrogenesis. Fibrosis progression, hepatic cell populations, and related molecular changes were evaluated.<br />Results: Both M0 and M1 BMDMs significantly ameliorated liver fibrosis, but M1 exhibited stronger therapeutic effects than M0. M2 macrophages were not effective on liver fibrosis. M1 macrophages reduced the number and activation of hepatic stellate cells (HSCs), which could be attributed at least partly to increased HSC apoptosis. M1 macrophages enhanced the recruitment of endogenous macrophages into fibrotic liver, which displayed the phenotype of Ly6C <superscript>lo</superscript> restorative macrophages and produced matrix metalloproteinases (MMPs) and hepatic growth factor (HGF) to enhance collagen degradation and hepatocyte proliferation, respectively. M1 macrophages also increased the number of total and activated natural killer (NK) cells in the fibrotic liver, which released TNF-related apoptosis-inducing ligand (TRAIL), inducing HSC apoptosis.<br />Conclusions: M1 macrophages, which modulate the immune microenvironment to recruit and modify the activation of endogenous macrophages and NK cells, are effective for cytotherapy in experimental liver fibrosis. Lay summary: M1 Bone marrow-derived macrophages (BMDMs) exhibit a stronger therapeutic effect by modulating the hepatic microenvironment to recruit and modify the activation of endogenous macrophages and natural killer (NK) cells, which likely lead to hepatic stellate cells (HSCs) apoptosis and hampered fibrogenesis.<br /> (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Antigens, Ly metabolism
Apoptosis
Carbon Tetrachloride toxicity
Cellular Microenvironment immunology
Disease Models, Animal
Hepatic Stellate Cells pathology
Killer Cells, Natural immunology
Liver Cirrhosis immunology
Liver Cirrhosis pathology
Macrophage Activation
Macrophages classification
Macrophages transplantation
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Cell- and Tissue-Based Therapy methods
Liver Cirrhosis therapy
Macrophages immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0641
- Volume :
- 67
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 28596109
- Full Text :
- https://doi.org/10.1016/j.jhep.2017.05.022