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


CONCLUSIONS
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.
Higashiyama
Reiichi
R
Liver Fibrosis Research Unit, Department of Community Health, Tokai University School of Medicine, Isehara, Japan.
Inagaki
Yutaka
Y
Hong
Yun Yu
YY
Kushida
Miwa
M
Nakao
Sachie
S
Niioka
Maki
M
Watanabe
Tetsu
T
Okano
Hideyuki
H
Matsuzaki
Yumi
Y
Shiota
Goshi
G
Okazaki
Isao
I
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000379:methods; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012075:Remission, Spontaneous
C485184:enhanced green fluorescent protein; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9