Basic—Liver, Pancreas, and Biliary TractNegligible Contribution of Bone Marrow-Derived Cells to Collagen Production During Hepatic Fibrogenesis in Mice
Section snippets
Mice
All animals used in the present study received humane care, and the experiments were approved by the Animal Experiment Committee of Tokai University. C57BL/6 mice were purchased from CLEA Japan Inc. (Tokyo, Japan). A transgenic mouse strain (COL/LUC) that contains the −17,000 to +54 region of the mouse upstream sequence of α2(I) collagen gene (COL1A2) linked to a firefly luciferase gene was previously described.14 The −17,000 to −15,450 COL1A2 sequence exhibits a strong enhancer activity that
BM-Derived Cells Migrating Into Fibrotic Liver Seldom Differentiate Into α-SMA-Positive Cells in Both Experimental Fibrosis Models
We first examined migration of BM cells into liver tissue in 2 mechanistically distinct fibrosis models introduced into CAG/EGFP-recipient mice. As previously reported,3 bridging fibrosis connecting the neighboring portal areas and central veins was formed, but complete cirrhosis was not established after 30 times of repeated CCl4 injections (Figure 2A). A large number of EGFP-expressing BM-derived cells migrated into the fibrotic liver 2 days after the last CCl4 injection, at peak fibrosis (
Discussion
In the present study, we have revealed an unexpectedly limited role of BM-derived cells in collagen production in 2 mechanistically distinct models of liver fibrosis. Although some of the BM-derived cells exhibited a mesenchymal morphology resembling myofibroblasts, the number of BM-derived α-SMA-positive cells was much smaller than previously reported. More importantly, specific and quantitative analyses of COL1A2 promoter activation by using a combination of EGFP and luciferase reporter genes
Acknowledgments
The authors thank Dr Benoit de Crombrugghe for his generous gift of transgenic collagen reporter mice, Dr Masaru Okabe for transgenic mice that constitutively express enhanced green fluorescent protein, and Dr Kiyoshi Higashi for his continuous support and helpful suggestions throughout the work.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan; a grant from the Scleroderma Research Committee of the Ministry of Health, Labour and Welfare, Japan; and a research grant from Mitsui Life Social Welfare Foundation.