Systemic Infusion of FLK1+ Mesenchymal Stem Cells Ameliorate Carbon Tetrachloride-Induced Liver Fibrosis in Mice

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Abstract
Fibrosis is the common end stage of most liver diseases, for which, unfortunately, there is no effective treatment available currently. It has been shown that mesenchymal stem cells (MSCs) from bone marrow (BM) could engraft in the lung after bleomycin exposure and ameliorate its fibrotic effects. This study was designed to evaluate the effect of Flk1+ MSCs from murine BM (termed here Flk1+ mMSCs) on fibrosis formation induced by carbon tetrachloride (CCl4). A CCl4-induced hepatic fibrosis model was used. Flk1+ mMSCs were systemically infused immediately or 1 week after mice were challenged with CCl4. Control mice received only saline infusion. Fibrosis index and donor-cell engraftment were assessed 2 or 5 weeks after CCl4 challenge. We found that Flk1+ mMSCs transplantation immediately, but not 1 week after exposure to CCl4, significantly reduced CCl4-induced liver damage and collagen deposition. In addition, levels of hepatic hydroxyproline and serum fibrosis markers in mice receiving immediate Flk1+ mMSCs transplantation after CCl4 challenge were significantly lower compared with those of control mice. More importantly, histologic examination suggested that hepatic damage recovery was much better in these immediately Flk1+ mMSCs-treated mice. Immunofluorescence, polymerase chain reaction, and fluorescence in situ hybridization analysis revealed that donor cells engrafted into host liver, had epithelium-like morphology, and expressed albumin, although at low frequency. These results suggest that Flk1+ mMSCs might initiate endogenous hepatic tissue regeneration, engraft into host liver in response to CCl4 injury, and ameliorate its fibrogenic effects.