Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice

Reiichi Higashiyama, Yutaka Inagaki, Yun Yu Hong, Miwa Kushida, Sachie Nakao, Maki Niioka, Tetsu Watanabe, Hideyuki Okano, Yumi Matsuzaki, Goshi Shiota, Isao Okazaki

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

Liver fibrosis is usually progressive, but it can occasionally be reversible if the causative agents are adequately removed or if patients are treated effectively. However, molecular mechanisms responsible for this reversibility of liver fibrosis have been poorly understood. To reveal the contribution of bone marrow (BM)-derived cells to the spontaneous regression of liver fibrosis, mice were treated with repeated carbon tetrachloride injections after hematopoietic reconstitution with enhanced green fluorescent protein (EGFP)-expressing BM cells. The distribution and characteristics of EGFP-positive (EGFP+) cells present in fibrotic liver tissue were examined at different time points after cessation of carbon tetrachloride intoxication. A large number of EGFP+ cells were observed in liver tissue at peak fibrosis, which decreased during the recovery from liver fibrosis. Some of them, as well as EGFP-negative (EGFP-) liver resident cells, expressed matrix metalloproteinase (MMP)-13 and MMP-9. Whereas MMP-13 was transiently expressed mainly in the cells clustering in the periportal areas, MMP-9 expression and enzymatic activity were detected over the resolution process in several different kinds of cells located in the portal areas and along the fibrous septa. Therapeutic recruitment of BM cells by granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced migration of BM-derived cells into fibrotic liver and accelerated the regression of liver fibrosis. Experiments using transgenic mice overexpressing hepatocyte growth factor (HGF) indicated that G-CSF and HGF synergistically increased MMP-9 expression along the fibrous septa. Conclusion: Autologous BM cells contribute to the spontaneous regression of liver fibrosis, and their therapeutic derivation could be a new treatment strategy for intractable liver fibrosis.

Original languageEnglish
Pages (from-to)213-222
Number of pages10
JournalHepatology
Volume45
Issue number1
DOIs
Publication statusPublished - 2007 Jan

Fingerprint

Matrix Metalloproteinases
Bone Marrow Cells
Liver Cirrhosis
Matrix Metalloproteinase 9
Matrix Metalloproteinase 13
Carbon Tetrachloride
Liver
Granulocyte Colony-Stimulating Factor
Hepatocyte Growth Factor
Therapeutics
Transgenic Mice
Cluster Analysis
enhanced green fluorescent protein
Fibrosis
Injections

ASJC Scopus subject areas

  • Hepatology

Cite this

Higashiyama, R., Inagaki, Y., Hong, Y. Y., Kushida, M., Nakao, S., Niioka, M., ... Okazaki, I. (2007). Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology, 45(1), 213-222. https://doi.org/10.1002/hep.21477

Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. / Higashiyama, Reiichi; Inagaki, Yutaka; Hong, Yun Yu; Kushida, Miwa; Nakao, Sachie; Niioka, Maki; Watanabe, Tetsu; Okano, Hideyuki; Matsuzaki, Yumi; Shiota, Goshi; Okazaki, Isao.

In: Hepatology, Vol. 45, No. 1, 01.2007, p. 213-222.

Research output: Contribution to journalArticle

Higashiyama, R, Inagaki, Y, Hong, YY, Kushida, M, Nakao, S, Niioka, M, Watanabe, T, Okano, H, Matsuzaki, Y, Shiota, G & Okazaki, I 2007, 'Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice', Hepatology, vol. 45, no. 1, pp. 213-222. https://doi.org/10.1002/hep.21477
Higashiyama, Reiichi ; Inagaki, Yutaka ; Hong, Yun Yu ; Kushida, Miwa ; Nakao, Sachie ; Niioka, Maki ; Watanabe, Tetsu ; Okano, Hideyuki ; Matsuzaki, Yumi ; Shiota, Goshi ; Okazaki, Isao. / Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. In: Hepatology. 2007 ; Vol. 45, No. 1. pp. 213-222.
@article{2ff67ef6ba24440581fc419e9ebd97af,
title = "Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice",
abstract = "Liver fibrosis is usually progressive, but it can occasionally be reversible if the causative agents are adequately removed or if patients are treated effectively. However, molecular mechanisms responsible for this reversibility of liver fibrosis have been poorly understood. To reveal the contribution of bone marrow (BM)-derived cells to the spontaneous regression of liver fibrosis, mice were treated with repeated carbon tetrachloride injections after hematopoietic reconstitution with enhanced green fluorescent protein (EGFP)-expressing BM cells. The distribution and characteristics of EGFP-positive (EGFP+) cells present in fibrotic liver tissue were examined at different time points after cessation of carbon tetrachloride intoxication. A large number of EGFP+ cells were observed in liver tissue at peak fibrosis, which decreased during the recovery from liver fibrosis. Some of them, as well as EGFP-negative (EGFP-) liver resident cells, expressed matrix metalloproteinase (MMP)-13 and MMP-9. Whereas MMP-13 was transiently expressed mainly in the cells clustering in the periportal areas, MMP-9 expression and enzymatic activity were detected over the resolution process in several different kinds of cells located in the portal areas and along the fibrous septa. Therapeutic recruitment of BM cells by granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced migration of BM-derived cells into fibrotic liver and accelerated the regression of liver fibrosis. Experiments using transgenic mice overexpressing hepatocyte growth factor (HGF) indicated that G-CSF and HGF synergistically increased MMP-9 expression along the fibrous septa. Conclusion: Autologous BM cells contribute to the spontaneous regression of liver fibrosis, and their therapeutic derivation could be a new treatment strategy for intractable liver fibrosis.",
author = "Reiichi Higashiyama and Yutaka Inagaki and Hong, {Yun Yu} and Miwa Kushida and Sachie Nakao and Maki Niioka and Tetsu Watanabe and Hideyuki Okano and Yumi Matsuzaki and Goshi Shiota and Isao Okazaki",
year = "2007",
month = "1",
doi = "10.1002/hep.21477",
language = "English",
volume = "45",
pages = "213--222",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice

AU - Higashiyama, Reiichi

AU - Inagaki, Yutaka

AU - Hong, Yun Yu

AU - Kushida, Miwa

AU - Nakao, Sachie

AU - Niioka, Maki

AU - Watanabe, Tetsu

AU - Okano, Hideyuki

AU - Matsuzaki, Yumi

AU - Shiota, Goshi

AU - Okazaki, Isao

PY - 2007/1

Y1 - 2007/1

N2 - Liver fibrosis is usually progressive, but it can occasionally be reversible if the causative agents are adequately removed or if patients are treated effectively. However, molecular mechanisms responsible for this reversibility of liver fibrosis have been poorly understood. To reveal the contribution of bone marrow (BM)-derived cells to the spontaneous regression of liver fibrosis, mice were treated with repeated carbon tetrachloride injections after hematopoietic reconstitution with enhanced green fluorescent protein (EGFP)-expressing BM cells. The distribution and characteristics of EGFP-positive (EGFP+) cells present in fibrotic liver tissue were examined at different time points after cessation of carbon tetrachloride intoxication. A large number of EGFP+ cells were observed in liver tissue at peak fibrosis, which decreased during the recovery from liver fibrosis. Some of them, as well as EGFP-negative (EGFP-) liver resident cells, expressed matrix metalloproteinase (MMP)-13 and MMP-9. Whereas MMP-13 was transiently expressed mainly in the cells clustering in the periportal areas, MMP-9 expression and enzymatic activity were detected over the resolution process in several different kinds of cells located in the portal areas and along the fibrous septa. Therapeutic recruitment of BM cells by granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced migration of BM-derived cells into fibrotic liver and accelerated the regression of liver fibrosis. Experiments using transgenic mice overexpressing hepatocyte growth factor (HGF) indicated that G-CSF and HGF synergistically increased MMP-9 expression along the fibrous septa. Conclusion: Autologous BM cells contribute to the spontaneous regression of liver fibrosis, and their therapeutic derivation could be a new treatment strategy for intractable liver fibrosis.

AB - Liver fibrosis is usually progressive, but it can occasionally be reversible if the causative agents are adequately removed or if patients are treated effectively. However, molecular mechanisms responsible for this reversibility of liver fibrosis have been poorly understood. To reveal the contribution of bone marrow (BM)-derived cells to the spontaneous regression of liver fibrosis, mice were treated with repeated carbon tetrachloride injections after hematopoietic reconstitution with enhanced green fluorescent protein (EGFP)-expressing BM cells. The distribution and characteristics of EGFP-positive (EGFP+) cells present in fibrotic liver tissue were examined at different time points after cessation of carbon tetrachloride intoxication. A large number of EGFP+ cells were observed in liver tissue at peak fibrosis, which decreased during the recovery from liver fibrosis. Some of them, as well as EGFP-negative (EGFP-) liver resident cells, expressed matrix metalloproteinase (MMP)-13 and MMP-9. Whereas MMP-13 was transiently expressed mainly in the cells clustering in the periportal areas, MMP-9 expression and enzymatic activity were detected over the resolution process in several different kinds of cells located in the portal areas and along the fibrous septa. Therapeutic recruitment of BM cells by granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced migration of BM-derived cells into fibrotic liver and accelerated the regression of liver fibrosis. Experiments using transgenic mice overexpressing hepatocyte growth factor (HGF) indicated that G-CSF and HGF synergistically increased MMP-9 expression along the fibrous septa. Conclusion: Autologous BM cells contribute to the spontaneous regression of liver fibrosis, and their therapeutic derivation could be a new treatment strategy for intractable liver fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=33846453528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846453528&partnerID=8YFLogxK

U2 - 10.1002/hep.21477

DO - 10.1002/hep.21477

M3 - Article

VL - 45

SP - 213

EP - 222

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 1

ER -