Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis

Background/Aims

Hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis. However, their origin is still unknown. We tested the hypothesis that bone marrow (BM) contributes to the population of HSCs.

Methods

Chimeric mice transplanted with donor BM from collagen α1(I)-GFP⁺ reporter mice were subjected to the bile duct ligation (BDL)-induced liver injury.

Results

In response to injury, BM-derived collagen-expressing GFP⁺ cells were detected in liver tissues of chimeric mice. However, these cells were not activated HSCs in that they did not express α-smooth muscle actin or desmin and could not be isolated with the HSC fraction. Meanwhile, the majority of these BM-derived cells co-expressed collagen-GFP⁺ and CD45⁺, suggesting that these cells represent a unique population of fibrocytes. Consistent with their lymphoid origin, the number of GFP⁺CD45⁺ fibrocytes found in BM and spleen of chimeric mice increased in response to injury. Fibrocytes cultured in the presence of TGF-β1 differentiated into SMA⁺desmin⁺ collagen-producing myofibroblasts, potentially contributing to liver fibrosis.

Conclusions

In response to the BDL-induced liver injury: (i) HSCs do not originate in the BM; (ii) collagen-producing fibrocytes are recruited from the BM to damaged liver.

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.