Abstract
Activated fibroblasts are key contributors to the fibrotic extracellular matrix accumulation during liver fibrosis. The origin of such fibroblasts is still debated, although several studies point to stellate cells as the principal source. The role of adult hepatocytes as contributors to the accumulation of fibroblasts in the fibrotic liver is yet undetermined. Here, we provide evidence that the pro-fibrotic growth factor, TGF-beta1, induces adult mouse hepatocytes to undergo phenotypic and functional changes typical of epithelial to mesenchymal transition (EMT). We perform lineage-tracing experiments using AlbCre. R26RstoplacZ double transgenic mice to demonstrate that hepatocytes which undergo EMT contribute substantially to the population of FSP1-positive fibroblasts in CCL(4)-induced liver fibrosis. Furthermore, we demonstrate that bone morphogenic protein-7 (BMP7), a member of the TGFbeta superfamily, which is known to antagonize TGFbeta signaling, significantly inhibits progression of liver fibrosis in these mice. BMP7 treatment abolishes EMT-derived fibroblasts, suggesting that the therapeutic effect of BMP7 was at least partially due to the inhibition of EMT. These results provide direct evidence for the functional involvement of adult hepatocytes in the accumulation of activated fibroblasts in the fibrotic liver. Furthermore, our findings suggest that EMT is a promising therapeutic target for the attenuation of liver fibrosis.
Highlights
Liver cirrhosis is still the sixth most common cause of death among United States citizens from ages 25 to 64 [1]
During advanced stages of fibrosis, both ␣SMA-positive cells and fibroblast-specific protein-1 (FSP1)-positive cells substantially accumulate in the areas of fibrotic septae dent stellate cells and fibroblasts or via shedding from vascular smooth muscle cells, FSP1-positive fibroblasts have been shown to derive by a significant extend from resident epithelia via epithelial-mesenchymal transition
We provide evidence that hepatocyte-derived fibroblasts are an additional and significant lineage of mesenchymal cells that contribute to progression of liver fibrosis
Summary
Liver cirrhosis is still the sixth most common cause of death among United States citizens from ages 25 to 64 [1]. We perform lineage-tracing experiments using AlbCre. R26RstoplacZ double transgenic mice to demonstrate that hepatocytes which undergo EMT contribute substantially to the population of FSP1-positive fibroblasts in CCL4-induced liver fibrosis. Immunofluorescence double-labeling experiments using antibodies specific to FSP1 and Collagen III revealed that FSP1-positive fibroblasts accumulate during fibrosis progression, predominantly in areas of collagen III deposition (Fig. 1, A–C).
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