Reply:
Authors: Yutaka Inagaki, Reiichi Higashiyama, Tetsu Watanabe, Isao Okazaki
Journal: Hepatology (2007)

We thank Dr. Russo and his colleagues for their interest in our recent article describing the expression of matrix metalloproteinases (MMPs) by bone marrow (BM)–derived cells and their possible contribution to the regression of liver fibrosis.1 We totally agree that BM contains pluripotential stem/progenitor cells and diverse cell types with different functions.2 In contrast to the beneficial role of BM-derived cells in the resolution of fibrosis, a number of experimental and human studies using BM transplantation with sex-mismatched3, 4 or genetically marked cells5, 6 have indicated that they express collagen and participate in the progression of liver fibrosis. In this study, we performed a series of confocal laser scanning microscopy examinations using the emission fingerprinting method, which eliminated the background autofluorescence and detected only the specific fluorescent signals. With this careful consideration, we reported that there were few, if any, BM-derived cells expressing α-smooth muscle actin (αSMA), a marker of activated hepatic stellate cells (HSCs) producing collagen in fibrotic liver.1 These findings do not deny collagen production by BM-derived cells but rather indicate the heterogeneity of collagen-producing cells in terms of their origin and differentiation status.7 A recent study has shown that some of the BM-derived collagen-producing cells exhibit the feature of fibrocytes.6 Those cells did not express αSMA in migrating fibrous liver tissue, nor were they detected in the HSC fraction isolated from the fibrotic liver.6 The lack of αSMA expression in BM-derived collagen-producing cells has also been reported in bleomycin-induced lung fibrosis.8 In addition, it is now well recognized that activated HSCs are not the only source of collagen in fibrotic liver, but different types of cells such as portal fibroblasts express collagen and participate in the progression of liver fibrosis, depending on the etiology of the liver injury and fibrosis.9 Taken together, the results of our study may indicate that αSMA-negative BM-derived cells produce collagen at peak fibrosis. More importantly, if BM contains pluripotential stem/progenitor cells and diverse cell types with both profibrotic and antifibrotic phenotypes, an attractive approach to treating liver fibrosis could be the regulation of BM cell differentiation and a switch of their phenotypes from collagen production to MMP expression. We totally agree that BM transplantation has a number of problems and limitations in its clinical use for advanced cirrhosis, not only because of its invasive procedure and potentially carcinogenic property10 but also because of the bidirectional effects of BM-derived cells on liver fibrosis described here. Thus, work is now in progress in our laboratory to elucidate the mechanisms of differential or coordinate expression of collagen and MMPs during the progression and regression of liver fibrosis and subsequently to characterize the humoral factors and small-molecule compounds that modify the differentiation of BM-derived cells. Considering that most of the MMP-13–expressing cells and approximately half of the MMP-9–producing cells were negative for any markers of liver resident cells and considered relatively undifferentiated,1 we believe that BM stem/progenitor cells could be a good target for such a safer and less invasive therapy for intractable liver fibrosis. Yutaka Inagaki*, Reiichi Higashiyama*, Tetsu Watanabe*, Isao Okazaki , * Liver Fibrosis Research Unit, Department of Community Health, Tokai University School of Medicine, Kanagawa, Japan, Sanno Hospital, International University of Health and Welfare, Tokyo, Japan.