Clarification of the mechanism of differentiation from hematopoietic stem cell-derived cells to hepatic stellate cells

平成20~22年度科学研究費補助金(基盤研究(C))研究成果報告書我々は四塩化炭素による肝傷害時に造血幹細胞由来の細胞が肝星細胞に分化しうることを明かにしたが、どの細胞系列のどの分化段階の細胞が真の肝星細胞の前駆細胞であるかは不明あった。四塩化炭素により肝傷害を与えたマウスに、EGFPマウスの骨髄や脾臓から分離し好中球、単球、好酸球、B細胞、T細胞を輸注するモデルを用いてEGFP陽性肝星細胞の出を検討したところ、単球を輸注したマウスの肝臓でのみEGFP陽性肝星細胞を検出した。こことから単球が肝星細胞の前駆細胞と考えられる。単球の傷害肝への侵入に関連する分子とてケモカインのMCP・1がある。CCR2は単球に発現しているMCP-1の受容体であるが、そantagonistが単球からの肝星細胞への分化に与える効果を検討したところ、傷害肝におい噛EGFP陽性肝星細胞は減少し、線維化も抑制された。We previously clarified that hematopoietic stem cell-derived cells were abele to differentiate into hepatic stellate cells (HpSCs) during carbon tetrachloride (CCl_4)-induced iver injury. Which lineage of cells are true precursors of HpSCs remains unknown. We idoptively transferred neutrophils, monocytes, eosinophils, B cells, or T cells, which were isolated rom enhanced green fluorescent protein (EGFP)-transgenic mice, into CCl_4-injured non-transgenic nice. In the livers of mice given monocytes, EGFP^+ HpSCs were detected. This suggest that a proportion of monocytes are precursors of HpSCs. Monocyte chemoattractant protein-1 (MCP-1) is bought to be associated with the invasion of monocytes into injured liver. CCR2, a receptor for vICP-1, is expressed on monocytes. We examined the effect of CCR2 antagonist against the lifferentiation of monocytes into HpSCs and found that the antagonist suppressed the number of EGFP^+ HpSCs and the area of fibrosis in injured liver