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Matrix Metalloproteinase-1 Expressed by Infiltrating Monocyte Progenitor Cells to Liver Promotes Human Nonalcoholic Steatohepatitis

67 Pages Posted: 25 Nov 2019

See all articles by Isao Okazaki

Isao Okazaki

International University of Health and Welfare Hospital (IUHW) - Department of Internal Medicine

Shinsuke Shibata

Keio University

Takayo Yanagawa

Tokai University

Hiroaki Yokomori

Kitasato University - Division of Internal Medicine

Wataru Ando

Kitasato University

Akira Sonoda

Keio University

Norihiko Suzuki

International University of Health and Welfare Hospital (IUHW)

Eigoro Yamanouchi

International University of Health and Welfare Hospital (IUHW)

Shinya Okada

International University of Health and Welfare Hospital (IUHW)

Shinichi Kamikura

International University of Health and Welfare Hospital (IUHW)

Kazuaki Hachimura

International University of Health and Welfare Hospital (IUHW)

Katsuya Otori

Kitasato University

Yutaka Suzuki

International University of Health and Welfare Hospital (IUHW)

Hideyuki Okano

Keio University

Yutaka Inagaki

Tokai University

More...

Abstract

Background: One quarter of global adults by overeating and reduced physical activity cause nonalcoholic fatty liver, and progress to nonalcoholic steatohepatitis (NASH), in which 10% of cases lead to liver cirrhosis and/or hepatocellular carcinoma. Adequate therapeutic option is urgent. We previously reported that matrix metalloproteinase-1 (MMP-1) expression in monocytes (MCs) and other types of cells in NASH livers is associated with disease progression. To test the hypothesis that bone marrow-derived monocytes (BMMCs) secrete exosomes with MMP-1 before their infiltration into steatosis liver, we examined MMP-1 mRNA and protein expression in circulating BMMCs.

Methods: Twenty-nine NASH patients and 26 non-NASH patients were recruited in this study. Confocal laser scanning microscopic (CLSM) and immune-electron microscopic examinations (IEM), and fluorescence-activated cell sorting of CD34+ BMMCs were performed. Peripheral CD45+CD14+CD34+ cells were co-cultured with steatosis hepatocytes (HCs) isolated from NASH liver.

Findings: IEM revealed that MCs were the earliest to acquire an MMP-1-expressing phenotype amongst all investigated cell types. CLSM showed that MMP-1 expression in Kupffer cells, hepatic stellate cells, progenitor cells, HCs, and endothelial cells were observed in subsequent to MCs. In advanced stage of NASH, OV-6- or CK19-positive hepatic progenitor cells around lethal HCs showed strong staining for MMP-1. These results suggested that MMP-1 expressed in progenitor cells may contribute to regeneration of injured liver, while MMP-1 up-regulation in hepatic stellate cells caused their activation leading to fibrosis. Unlike our initial hypothesis, circulating BMMCs did not express significant amounts of MMP-1 mRNA or protein before their infiltration into steatosis liver. By contrast, co-culture with steatosis HCs induced MMP-1 expression in otherwise MMP-1-negative CD34+ BMMCs. This phenotypic change in MMP-1 expression was the most pronounced in CD45+CD14+CD34+ cells.

Interpretation: The results of the present study implicated MMP-1 expression by the monocyte progenitor cell population after their migration into steatosis liver in NASH pathogenesis.

Funding Statement: This work is supported by grant no. IUHW 2016-24 and -25 from Mr. Takeshi Mori and Mrs. Eiko Mori to Dr. Okazaki.

Declaration of Interests: The authors have declared that no conflict of interest exists.

Ethics Approval Statement: The study protocol was approved by the Ethics Committee of IUHW (13-B-136, February 22, 2016; 13-B-205, November 24, 2016; 13-B-229, April 27, 2017). All patients provided written formal informed consent for participation in this study.

Keywords: nonalcoholic steatohepatitis, matrix mealloproteinases, hepatic stellate cell, hepatic progenitor cell

Suggested Citation

Okazaki, Isao and Shibata, Shinsuke and Yanagawa, Takayo and Yokomori, Hiroaki and Ando, Wataru and Sonoda, Akira and Suzuki, Norihiko and Yamanouchi, Eigoro and Okada, Shinya and Kamikura, Shinichi and Hachimura, Kazuaki and Otori, Katsuya and Suzuki, Yutaka and Okano, Hideyuki and Inagaki, Yutaka, Matrix Metalloproteinase-1 Expressed by Infiltrating Monocyte Progenitor Cells to Liver Promotes Human Nonalcoholic Steatohepatitis (November 15, 2019). Available at SSRN: https://ssrn.com/abstract=3487786

Isao Okazaki (Contact Author)

International University of Health and Welfare Hospital (IUHW) - Department of Internal Medicine ( email )

Nasu-Shiobara City
Japan

Shinsuke Shibata

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Takayo Yanagawa

Tokai University

3-20-1 Orido
Shimizu-ku
Shizuoka, 424-8610
Japan

Hiroaki Yokomori

Kitasato University - Division of Internal Medicine

Kitamoto, 364-8501
Japan

Wataru Ando

Kitasato University

Tokyo
Japan

Akira Sonoda

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Norihiko Suzuki

International University of Health and Welfare Hospital (IUHW)

Nasu-Shiobara City
Japan

Eigoro Yamanouchi

International University of Health and Welfare Hospital (IUHW)

Nasu-Shiobara City
Japan

Shinya Okada

International University of Health and Welfare Hospital (IUHW)

Nasu-Shiobara City
Japan

Shinichi Kamikura

International University of Health and Welfare Hospital (IUHW)

Nasu-Shiobara City
Japan

Kazuaki Hachimura

International University of Health and Welfare Hospital (IUHW)

Nasu-Shiobara City
Japan

Katsuya Otori

Kitasato University

Tokyo
Japan

Yutaka Suzuki

International University of Health and Welfare Hospital (IUHW)

Nasu-Shiobara City
Japan

Hideyuki Okano

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Yutaka Inagaki

Tokai University

3-20-1 Orido
Shimizu-ku
Shizuoka, 424-8610
Japan

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