Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice.
BACKGROUND
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).


METHODS
A CCl(4)-induced hepatic fibrosis model was used. Flk1 mMSCs were systemically infused immediately or 1 week after mice were challenged with CCl(4). Control mice received only saline infusion. Fibrosis index and donor-cell engraftment were assessed 2 or 5 weeks after CCl(4) challenge.


RESULTS
We found that Flk1 mMSCs transplantation immediately, but not 1 week after exposure to CCl(4), significantly reduced CCl(4)-induced liver damage and collagen deposition. In addition, levels of hepatic hydroxyproline and serum fibrosis markers in mice receiving immediate Flk1 mMSCs transplantation after CCl(4) 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.


CONCLUSIONS
These results suggest that Flk1 mMSCs might initiate endogenous hepatic tissue regeneration, engraft into host liver in response to CCl(4) injury, and ameliorate its fibrogenic effects.
Fang
Baijun
B
Sino-American Collaborative Laboratory, State Key Lab of Experimental Haematology, Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Tissue Engineering Center, Chinese Academy of Medical Sciences, Tianjin, China.
Shi
Mingxia
M
Liao
Lianming
L
Yang
Shaoguang
S
Liu
Yuhao
Y
Zhao
Robert Chunhua
RC
D000199:Actins / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D005260:Female; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008297:Male; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000032:analysis; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D000199:Actins; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride; D040301:Vascular Endothelial Growth Factor Receptor-2