Recruitment of endogenous bone marrow mesenchymal stem cells towards injured liver

• Published in: Journal of cellular and molecular medicine 2010-06, Vol.14 (6b), p.1494-1508
• Main Authors: Chen, Ye, Xiang, Li‐Xin, Shao, Jian‐Zhong, Pan, Ruo‐Lang, Wang, Yu‐Xi, Dong, Xue‐Jun, Zhang, Guo‐Rong
• Format: Article
• Language: English
• Subjects: Adipocytes; Allografts; Animals; Antibodies - pharmacology; Biological Assay; Bone growth; Bone healing; Bone imaging; Bone marrow; Bone Marrow Cells - cytology; Bone marrow transplantation; Cell differentiation; Cell division; Cell fate; Cell migration; Cell Movement - drug effects; Chemokines; Chemotaxis; Cloning; CXCR4 protein; cytokine receptor; Cytokines; Down-regulation; Female; Fibrosis; Flow cytometry; Gene Expression Profiling; Gene Expression Regulation - drug effects; Green fluorescent protein; Green Fluorescent Proteins - metabolism; Hepatocytes; Hepatology; homing; Homing behavior; Liver; Liver - drug effects; Liver - injuries; Liver - pathology; Male; Medical research; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Original; Peripheral blood; Polymerase chain reaction; Receptors, Chemokine - antagonists & inhibitors; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; recruitment; Reverse Transcriptase Polymerase Chain Reaction; Stellate cells; Stem cell transplantation; Stem cells; Transgenic animals; Transgenic mice; Wound healing
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2009.00912.x

Recent studies suggest that mesenchymal stem cells (MSCs) possess a greater differentiation potential than once thought and that they have the capacity to regenerate damaged tissues/organs. However, the evidence is insufficient, and the mechanism governing the recruitment and homing of MSCs to these injured sites is not well understood. We first examined the MSCs circulating in peripheral blood and then performed chemotaxis, wound healing and tubule‐formation assays to investigate the migration capability of mouse bone marrow MSCs (mBM‐MSCs) in response to liver‐injury signals. In addition, BM‐MSCs from donor enhanced green fluorescent protein transgenic male mice were transplanted into liver‐injured co‐isogenic female recipients, either by intra‐bone marrow injection or through the caudal vein, to allow in vivo tracking analysis of the cell fate after transplantation. Donor‐derived cells were analysed by in vivo imaging analysis, PCR, flow cytometry and frozen sections. Microarray and real‐time PCR were used for chemokine/cytokine and receptor analyses. We successfully isolated circulating MSCs in peripheral blood of liver‐injured mice and provided direct evidence that mBM‐MSCs could be mobilized into the circulation and recruited into the liver after stimulation of liver injury. CCR9, CXCR4 and c‐MET were essential for directing cellular migration towards the injured liver. The recruited mBM‐MSCs may play different roles, including hepatic fate specification and down‐regulation of the activity of hepatic stellate cells which inhibits over‐accumulation of collagen and development of liver fibrosis. Our results provide new insights into liver repair involving endogenous BM‐MSCs and add new information for consideration when developing clinical protocols involving the MSCs.