Bone marrow cells in the liver: Diverse cells, diverse effects


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Bone Marrow Cells in the Liver: Diverse Cells, Diverse Effects

To the Editor:

We read with interest the report by Higashiyama et al.,1 who found that bone marrow (BM)–derived cells contributed to the regression of liver fibrosis in a murine model and that these cells were likely to be macrophages secreting matrix metalloproteinase (MMP)-9 and MMP-13. This agrees with previous work demonstrating a role for BM-derived macrophages in liver fibrosis resolution.2 Moreover, their observation that granulocyte colony-stimulating factor and hepatocyte growth factor accelerated this fibrolysis is consistent with a role for BM-derived cells and the antifibrotic properties of hepatocyte growth factor, respectively. These data, together with other reports from rodent models,3 are encouraging for the potential use of BM-derived cells for the therapy of liver fibrosis, and such approaches are being adopted in clinical protocols.4, 5 However, we were surprised that no role for BM cells in the fibrogenic process was noted. In particular, the authors found little evidence for BM-derived α-smooth muscle actin–positive cells (activated fibroblasts/myofibroblasts) following 90 days of a chronic carbon tetrachloride treatment. The hepatic stellate cell (HSC) has been the focus of efforts to identify the source of the extracellular matrix in liver fibrosis. Chronic liver injury results in HSC activation switching HSCs to a myofibroblast phenotype and collagen secretion. During the development of fibrosis in diverse organs, we and others have shown that BM contributes to the myofibroblast population (usually between 20% and 30%) in diverse organs,6 using experimental models of liver disease7–9 and studies of human liver tissue.10 Interestingly, we have also noted a relative lack of BM-derived α-smooth muscle actin–positive myofibroblasts during liver fibrosis regression,9 and the results from Higashiyama et al. may reflect the tissue analysis being restricted to a narrow timeframe. In light of this burgeoning evidence for a role of BM in fibrosis development, we feel that this article may, if taken in isolation, give a somewhat unbalanced viewpoint concerning the wholly beneficial effects of BM therapy. In particular, for the rational development of clinical protocols, it should be kept in mind that BM contains diverse cell types that may manifest both profibrotic and antifibrotic phenotypes, depending on both their differentiation potential and the phase of liver injury when they are used. A further issue requiring clarification is the nature of the BM-derived matrix metalloproteinase–producing cells. We note that this article suggests they are macrophages; conversely, previous studies have identified hepatocytes as the fibrolytic cells.3 This is clearly of considerable significance to the healing outcome in the liver.

Francesco P. Russo*, Yiannis N. Kallis†, Malcolm R. Alison‡, Stuart J. Forbes?, * Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy, † Department of Medicine, Imperial College London, London, UK, ‡ Centre for Diabetes and Metabolic Medicine, Queen Mary's School of Medicine and Dentistry, Institute of Cell and Molecular Science, London, UK, ? Tissue Fibrosis and Remodelling Laboratory, Medical Research Council/University of Edinburgh, Centre for Inflammation Research, Edinburgh, UK.