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J Thromb Haemost. 2013 May;11(5):963-74. doi: 10.1111/jth.12198.

Fibrocytes mediate intimal hyperplasia post-vascular injury and are regulated by two tissue factor-dependent mechanisms.

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Medical Research Council (MRC) Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK.



CD34(+) α-smooth muscle actin (SMA)(+) cells mediate intimal hyperplasia (IH) after mechanical endoluminal injury. We previously found that IH is tissue factor (TF) dependent. The precise phenotype of the CD34(+) cells mediating IH is unknown and the mechanisms of TF are also unknown.


To define the phenotype of cells mediating IH and compare the effects of inhibiting TF on different subsets of CD34(+) cells.


Endoluminal injury was induced in C57BL/6 and two strains of mice expressing a human tissue factor pathway inhibitor (hTFPI) fusion protein on different subsets of CD34(+) cells. Confocal microscopy, immunocytofluorescence and real-time PCR were used to determine phenotype.


Neointimal cells in C57BL/6 mice were defined as a subset of fibrocytes (CD34(+) CD45(+) collagen-1(+) ) expressing SMA, CD31, TIE-2, CXCR4 and CXCL12. Similar cells circulated post-injury and were also found in mice expressing hTFPI on CD34(+) CD31(+) cells, though in these mice, hTFPI inhibited CD31(+) fibrocyte hyperplasia, so no IH developed. Mice with hTFPI on all CD34(+) α-SMA(+) cells repaired arteries back to a pre-injured state. No CD31(+) fibrocytes were found in these mice unless an anti-hTFPI antibody was administered. Similar findings in protease activated receptor (PAR)-1-deficient mice suggested hTFPI prevented thrombin signaling through PAR-1. In vitro, thrombin increased the number of CD31(+) fibrocytes.


Inhibition of TF on CD31(+) fibrocytes inhibits IH whereas inhibition on all CD34(+) α-SMA(+) cells (or PAR-1 deficiency) inhibits the appearance of CD31(+) fibrocytes and promotes repair. These data enhance our understanding of IH and suggest novel ways to promote regenerative repair.

[Indexed for MEDLINE]
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