Cell-based therapy facilitates venous thrombus resolution

Summary

Endothelial progenitor cells (EPC) are involved in many healing processes in cardiovascular diseases and can be found in spontaneously resolving venous thrombi. The purpose of the present study was to investigate whether the therapeutic administration of EPC might enhance the resolution of venous thrombi. For this purpose, venous thrombosis was induced in the infrarenal inferior vena cava (IVC) in 28 athymic nude rats. Culture expanded EPC derived from human peripheral blood mononuclear cells were injected intravenously two and four days after thrombus induction. Recanalisation of the IVC and thrombus organisation were assessed by laser Doppler measurements of the blood flow and immunohistochemical detection of endothelialised luminal structures in the thrombus. EPC transplantation resulted in significantly enhanced thrombus neovascularisation (capillary density: 186.6 ± 26.7/HPF vs. 78 ± 12.3/HPF, p<0.01; area covered by capillaries: 8.9 ± 1.7 µm² vs. 2.5 ± 1.3 µm², p<0.01) and was accompanied by a substantial increase in intrathrombus blood flow (perfusion ratio: 0.7 ± 0.07 vs. 0.3 ± 0.08, p<0.02). These results were paralleled by augmented macrophage recruitment into resolving thrombi in the animals treated with EPC (39.4 ± 4.7/HPF vs. 11.6 ± 1.9/HPF, p<0.01). Our data suggest that EPC transplantation might be of clinical value to facilitate venous thrombus resolution in cases where current therapeutic options have limited success.

Keywords

Venous thrombosis - cell therapy - neovascularisation - endothelial progenitor cells - macrophages

^* These authors contributed equally.

• References

• 1 Modarai B, Burnand KG, Humphries J. et al. The role of neovascularisation in the resolution of venous thrombus. Thromb Haemost 2005; 93: 801-809.
• 2 Modarai B, Burnand KG, Sawyer B. et al. Endothelial progenitor cells are recruited into resolving venous thrombi. Circulation 2005; 111: 2645-2653.
• 3 Moldovan NI. Role of monocytes and macrophages in adult angiogenesis: a light at the tunnel’s end. J Hematotherap Stem Cell Res 2002; 11: 179-194.
• 4 Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003; 9: 702-712.
• 5 Kamihata H, Matsubara H, Nishiue T. et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001; 104: 1046-1052.
• 6 Kawamoto A, Gwon HC, Iwaguro H. et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001; 103: 634-637.
• 7 Zhang ZG, Zhang L, Jiang Q. et al. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circulation Res 2002; 90: 284-288.
• 8 Kalka C, Masuda H, Takahashi T. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularisation. Proc Natl Acad Sci USA 2000; 97: 3422-3427.
• 9 Wakefield TW, Linn MJ, Henke PK. et al. Neovascularization during venous thrombosis organization: a preliminary study. J Vasc Surg 1999; 30: 885-892.
• 10 van Ramshorst B, van Bemmelen PS, Hoeneveld H. et al. Thrombus regression in deep venous thrombosis. Quantification of spontaneous thrombolysis with duplex scanning, Circulation 1992; 86: 414-419.
• 11 Hirano K, Shimono T, Imanaka-Yoshida K. et al. Method of cell transplantation promoting the organization of intraarterial thrombus. Circulation 2005; 112: I111-116.
• 12 Moldovan NI. Tissular insemination of progenitor endothelial cells: the problem, and a suggested solution. Adv Exp Med Biol 2003; 522: 99-113.
• 13 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28: 387-391.
• 14 Varma MR, Moaveni DM, Dewyer NA. et al. Deep vein thrombosis resolution is not accelerated with increased neovascularisation. J Vasc Surg 2004; 40: 536-542.
• 15 Humphries J, McGuinness CL, Smith A. et al. Monocyte chemotactic protein-1 (MCP-1) accelerates the organization and resolution of venous thrombi. J Vasc Surg 1999; 30: 894-899.
• 16 Ali T, Humphries J, Burnand K. et al. Monocyte recruitment in venous thrombus resolution. J Vasc Surg 2006; 43: 601-608.
• 17 Henke PK, Varma MR, Deatrick KB. et al. Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularisation. Thromb Haemost 2006; 95: 272-281.
• 18 Waltham M, Burnand KG, Collins M. et al. Vascular endothelial growth factor and basic fibroblast growth factor are found in resolving venous thrombi. J Vasc Surg 2000; 32: 988-996.
• 19 Henke PK, Varga A, De S. et al. Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity in a mouse model. Arterioscler Thromb Vasc Biol 2004; 24: 1130-1137.
• 20 Henke PK, Wakefield TW, Kadell AM. et al. Inter-leukin-8 administration enhances venous thrombosis resolution in a rat model. J Surg Res 2001; 99: 84-91.
• 21 Waltham M, Burnand KG, Collins M. et al. Vascular endothelial growth factor enhances venous thrombus recanalisation and organisation. Thromb Haemost 2003; 89: 169-176.
• 22 Urbich C, Aicher A, Heeschen C. et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol 2005; 39: 733-742.