Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis☆
Introduction
Liver fibrosis, an outcome of many chronic liver diseases [1], is characterized by extensive deposition of extracellular matrix, mainly type I collagen [2]. Hepatic stellate cells (HSCs) are believed to play a major role in the pathogenesis of liver fibrosis [3]. In response to injury, quiescent HSCs undergo morphological and functional changes to become activated HSC with a myofibroblastic phenotype that express high amount of type I collagen [4]. However, it is still unknown whether hepatic HSCs proliferate in the liver or originate in the BM (bone marrow) and migrate to liver in response to injury. Recently, conversion of BM cells into several hepatic cell populations, e.g. hepatic oval cells, hepatocytes, sinusoidal endothelial cells, etc., has been intensively studied [5], [6], [7], [8], [9]. Conversion of BM progenitors into highly specialized cells of distinct origin occurs either due to transdifferentiation [6] or cellular fusion in the target organs [6], [10]. However, differentiation without “change of the cell fate” has been described for a subset of collagen-producing cells designated as fibrocytes, a unique population of collagen producing cells identified in peripheral blood [11], [12], [13], [14]. This study tested the hypothesis that HSCs and/or other collagen-producing cells [15], [16] arise from a population of cells originating in the bone marrow. Using BM chimeric mice expressing GFP under control of the collagen α1(I) promoter [17], [18], we specifically investigated the BM contribution to the population of HSCs and non-HSC collagen-producing cells in response to bile duct ligation (BDL)-induced hepatic injury.
Section snippets
Generation of BM chimeric mice and induction of liver injury
Wild type C57BL/6 (B6) mice (wt) were purchased from The Jackson Laboratory (Bar Harbor, Maine, USA). Transgenic mice, expressing GFP driven by collagen α1(I) promoter (Col), were previously characterized [17], [18]. BM chimeric mice were generated as previously described [5], [19]. Mice were allowed to recuperate for 2 months prior to induction of liver fibrosis. BM engraftment in Col-into-wt mice was confirmed by Southern blot analysis of BM-derived genomic DNA using 32P-radiolabeled gfp
Collagen producing cells of BM origin are present in fibrotic liver
We performed a series of bone marrow transplantations (BMT) in mice to determine whether hepatic stellate cells (HSCs) or other collagen producing cells originated in the BM in response to bile duct ligation (BDL), a well-established model of liver injury (Fig. 1A). To monitor migration of BM-derived collagen-expressing cells to injured liver, reporter mice expressing GFP under the collagen α1(I) promoter (Col mice) were used [17], [18]. In a first set of experiments, BM from Col mice was
Discussion
Hepatic stellate cells are the main producers of collagen in the injured liver. However, it has been suggested that fibroblasts in the liver also contribute to collagen-production after injury. The origins of HSCs and hepatic fibroblasts remain unresolved. It has been suggested that HSCs are bone marrow-derived [27]. Even though HSCs express several markers that are typically found on BM-derived cells such as ICAM, CCR5 and CD40, they also display neural crest markers such as synaptophysin and
Acknowledgements
We wish to thank Lin Yang and the Molecular Pathology Facility of the Herbert Irving Cancer Center of Columbia University provided superb histology service. We acknowledge Stella Stefanova for excellent technical assistance.
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The authors who have taken part in the research of this paper have no relationship with the manufacturers of the drug involved either in the past or present. The authors state that they did not receive funding from the manufacturers to carry out their research. The authors received funding from NIH which enabled them to carry out their study.