The significance of CD14+ monocytes in peripheral blood stem cells for the treatment of rat liver cirrhosis.
OBJECTIVE
Circulating monocytes have been exploited as an important progenitor cell resource for hepatocytes in vitro and are instrumental in the removal of fibrosis. We investigated the significance of monocytes in peripheral blood stem cells (PBSC) for the treatment of liver cirrhosis.


METHODS
Rat CD14+ monocytes in PBSC were mobilized with granulocyte-colony-stimulating factor (G-CSF) and harvested by magnetic cell sorting (MACS). Female rats with carbon tetrachloride (CCl₄-induced liver cirrhosis were injected CM-DiI-labeled monocytes, CD14⁻ cells (1 x 10⁷ cells/rat) or saline via the portal vein.


RESULTS
Rat CD14+ and CD11b+ monocytes in PBSC were partly positive for CD34, CD45, CD44, Oct3/4 and Sox2, suggesting monocytes with progenitor capacity. Compared with CD14⁻ cell-infused and saline-injected rats, rats undergoing monocyte transplantation showed a gradually increased serum albumin level and decreased portal vein pressure, resulting in a significantly improved survival rate. Meanwhile, monocyte transplantation apparently attenuated liver fibrosis by analysis for fibronectin, α2-(1)-procollagen, α-smooth muscle aorta (SMA) and transforming growth factor (TGF)-β. Transplanted monocytes mainly clustered in periportal areas of liver, in which 1.8% cells expressed hepatocyte marker albumin and CK18. The expression level of hepatocyte growth factor (HGF), TGF-α, extracellular matrix (EGF) and vascular endothelial growth factor (VEGF) increased, while monocyte transplantation enhanced hepatocyte proliferation. On the other hand, the activities and expression of matrix metalloproteinases (MMP) increased while tissue inhibitor of metalloproteinase (TIMP)-1 expression significantly reduced in monocyte-transplanted livers. Some transplanted monocytes expressed MMP-9 and -13.


CONCLUSIONS
The data suggest that CD14+ monocytes in PBSC contribute to hepatocyte regeneration and extracellular matrix (ECM) remodeling in rat liver cirrhosis much more than CD14⁻ cells, and might offer a therapeutic alternative for patients with liver cirrhosis.
Wang
Jingbo
J
Division of Hepatology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shannxi Province, China.
Zhou
Xinmin
X
Cui
Lina
L
Yan
Li
L
Liang
Jie
J
Cheng
Xin
X
Qiao
Lijuan
L
Shi
Yongquan
Y
Han
Zheyi
Z
Cao
Yunxin
Y
Han
Ying
Y
Fan
Daiming
D
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D008297:Male; D055017:Monocyte-Macrophage Precursor Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains
D015415:Biomarkers; D018950:Lipopolysaccharide Receptors; D016179:Granulocyte Colony-Stimulating Factor; D002251:Carbon Tetrachloride