Bone Marrow Mesenchymal Stem Cells Reverse Liver Damage in a Carbon Tetrachloride-induced Mouse Model of Chronic Liver Injury.
OBJECTIVE
The aim of this study was to investigate the effect of bone-marrow mesenchymal stem cells (BMSCs) on repair of liver damage in a carbon tetrachloride (CCl4)-induced mouse model of chronic liver damage.


METHODS
Green fluorescent protein (GFP)-expressing BMSCs, isolated from GFP transgenic mice, were transplanted into mice with chronic liver damage induced by CCl4 The GFP-expressing BMSCs in livers were detected by fluorescence microscopy. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured for assessment of liver function. Liver histopathology was performed to assess liver damage. mRNA and protein expression of liver-associated markers albumin (Alb) and alpha-fetoprotein (Afp) were detected to confirm the hepatic differentiation of BMSCs in the liver. Immunostaining for the expression of interleukin-10 (IL-10) and matrix metallopeptidase-9 (MMP-99), and enzyme-linked immunosorbent assay for the secretion of type III collagen and lamininin was carried out.


RESULTS
After BMSC transplantation, GFP-expressing BMSCs were detected in the peri-portal and injured areas of the CCL4-injured liver. mRNA and protein expressions of Alb and Afp were significantly increased in BMSC-transplanted liver. Mice treated with BMSCs displayed reduced serum levels of ALT and AST, and CCl4-induced histopathological changes in livers were repaired. BMSC transplantation increased the production of IL-10 and inhibited the expression of MMP-9, as well as the secretion of type III collagen and lamininin.


CONCLUSIONS
BMSCs transplanted into mice can migrate into damaged liver, differentiate into hepatocytes and promote recovery from chemically-induced liver damage. Promotion of IL-10 and inhibition of MMP-9 by transplanted BMSCs may be involved in the anti-inflammatory and anti-fibrotic action of BMSCs.
Liver Disease Center of PLA, Department of Infectious Disease, Nanjing University of Chinese Medicine Affiliated Bayi Hospital, Nanjing, P.R. China maorongwang@126.com all@anticancer.com.
Maorong
M
Wang
Liver Disease Center of PLA, Department of Infectious Disease, Nanjing University of Chinese Medicine Affiliated Bayi Hospital, Nanjing, P.R. China.
Xin
X
Zhang
Liver Disease Center of PLA, Department of Infectious Disease, Nanjing University of Chinese Medicine Affiliated Bayi Hospital, Nanjing, P.R. China.
X I
XI
Xiong
Liver Disease Center of PLA, Department of Infectious Disease, Nanjing University of Chinese Medicine Affiliated Bayi Hospital, Nanjing, P.R. China.
Zhiguo
Z
Yang
Liver Disease Center of PLA, Department of Infectious Disease, Nanjing University of Chinese Medicine Affiliated Bayi Hospital, Nanjing, P.R. China.
Ping
P
Li
Liver Disease Center of PLA, Department of Infectious Disease, Nanjing University of Chinese Medicine Affiliated Bayi Hospital, Nanjing, P.R. China.
Jie
J
Wang
Origin Biosciences Inc., Nanjing, P.R. China.
Y U
YU
Sun
Origin Biosciences Inc., Nanjing, P.R. China AntiCancer Inc., San Diego, CA, U.S.A.
Zhijian
Z
Yang
AntiCancer Inc., San Diego, CA, U.S.A. Department of Surgery, University of California San Diego, San Diego, CA, U.S.A. maorongwang@126.com all@anticancer.com.
Robert M
RM
Hoffman
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism
D000509:alpha-Fetoproteins; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020780:Matrix Metalloproteinase 9
Bone marrow; CCl4; liver damage; mesenchymal stem cells; mouse model; repair; transplantation