LFA-1 and VLA-4 involved in human high proliferative potentialendothelial progenitor cells homing to ischemic tissue

Summary

Cumulative evidences have revealed that endothelial progenitor cell (EPC) transplantation can promote the neovascularization in ischemic tissue, but the mechanism of EPCs homing to the site of ischemia is poorly understood. In this study, to investigate the mechanism of human umbilical cord blood-derived high proliferative potential-endothelial progenitor cells (HPP-EPCs) homing to ischemic tissue we evaluated the expression of lymphocyte function-associated antigen-1 (LFA-1, or CD11a/CD18) and very late antigen-4 (VLA-4, or CD49d/CD29) in EPCs and the changes of expression level of their ligands, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), in ischemic tissue and performed the adhesion and migration assays to analyze the interaction between the receptors and ligands. Furthermore, we studied the roles of LFA-1 and VLA-4 in EPC homing in an ischemic model of mice. The results show that LFA-1 andVLA-4 were expressed in HPPEPCs and ICAM-1 and VCAM-1 were expressed in vessel endothelium in ischemic tissues. The pre-incubation of HPP-EPCs with neutralizing antibodies against CD11a or CD49d reduced adhesion and migration of HPP-EPCs in vitro and reduced recovery of hind-limb blood flow, capillary density and incorporation of HPP-EPC into ischemic tissues in vivo. Furthermore, the pre-incubation of HPP-EPCs with the combination of CD11a and CD49d antibodies led to synergistically negative effects on adhesion and transmigration of HPP-EPCs in vitro, and on the homing of HPP-EPCs to ischemic tissue and on neovascularization capacity in vivo. These results indicate that LFA-1 andVLA-4 are involved in HPP-EPC homing to ischemic tissues.

Keywords

Endothelial progenitor cells - homing - ischemia - adhesion molecules

• Reference

• 1 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-57.
• 2 Asahara T, Murohar T, Sullivan A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-7.
• 3 Asahara T, Masuda H, Takahashi T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85: 221-8.
• 4 Shi Q, Rafii S, Wu MHD. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 1998; 92: 362-7.
• 5 Grant MB, May WS, Caballero S. et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 2002; 08: 607-12.
• 6 Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003; 09: 702-12.
• 7 Aicher A, Heeschen C, Mildner-Rihm C. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003; 09: 1370-6.
• 8 Lyden D, Hattori K, Dias S. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001; 07: 1194-201.
• 9 Takahashi T, Kalka C, Masuda H. et al. Ischemiaand cytokine-induced mobilization of bone marrowderived endothelial progenitor cells for neovascularization. Nat Med 1999; 05: 434-8.
• 10 Shintani S, Murohara T, Ikeda H. et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001; 103: 2776-9.
• 11 Asahara T, Takahashi T, Masuda H. et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18: 3964-72.
• 12 Kalka C, Masuda H, Takahashi T. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97: 3422-7.
• 13 Kocher AA, Schuster MD, Szabolcs MJ. et al. Neovascularization of ischemic myocardium by human bone marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001; 07: 430-6.
• 14 Kawamoto A, Gwon HC, Iwaguro H. et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001; 103: 634-7.
• 15 Assmus B, Schachinger V, Teupe C. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCAREAMI). Circulation 2002; 106: 3009-17.
• 16 Aicher A, Brenner W, Zuhayra M. et al. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 2003; 107: 2134-9.
• 17 Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004; 95: 343-53.
• 18 Hur J, Yoon CH, Kim HS. et al. Characteristic of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 2004; 24: 288-93.
• 19 Muller WA. Leukocyte-endothelial cell interactions in the inflammatory response. Lab Invest 2002; 82: 521-34.
• 20 Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 2004; 04: 432-44.
• 21 Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 2005; 05: 546-59.
• 22 Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005; 06: 1182-90.
• 23 Chavakis E, Aicher A, Heeschen C. et al. Role of β2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 2005; 201: 63-72.
• 24 Jin H, Aiyer A, Su J. et al. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J Clin Invest 2006; 116: 652-62.
• 25 Gulati R, Jevremovic D, Peterson TE. et al. Diverse origin and function of cells with endothelial phenotype obtain from adult human blood. Circ Res 2003; 93: 1023-5.
• 26 Ingram DA, Mead LE, Tanaka H. et al. Identification of a novel hierarchy of endothelial progenitor cells utilizing human peripheral and umbilical cord blood. Blood 2004; 104: 2752-60.
• 27 Duan HX, Cheng LM, Lu GX. Angiogenic potential difference between two types of endothelial progenitor cells from human umbilical cord blood. Cell Biol Int. 2006 prepublished online at http://dx.doi.org/10.1016/j.cellbi.2006.08.002
• 28 Wang QR, Yan Y, Wang BH. Establishment of murine bone marrow derived endothelial cell line. J Exp Hematol 1997; 05: 360-6.
• 29 Parkin A, Robinson PJ, Martinez D. et al. Radionuclide limb blood flow in peripheral vascular disease: a review of 1100 measurements. Nucl Med Commun 1991; 12: 835-51.
• 30 Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76: 301-14.
• 31 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-101.
• 32 Schenkel AR, Mamdouh Z, Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 2004; 05: 393-400.
• 33 Becker PS, Nilsson SK, Li Z. et al. Adhesion receptor expression by hematopoietic cell lines and murine progenitors: modulation by cytokines and cell cycle status. Exp Hematol 1999; 27: 533-41.
• 34 Orschell-Traycoff CM, Hiatt K, Dagher RN. et al. Homing and engraftment potential of Sca-1 (+) lin (-) cells fractionated on the basis of adhesion molecule expression and position in cell cycle. Blood 2000; 96: 1380-7.
• 35 Elices MJ, Osborn L, Takada Y. et al. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 ata site distinct from the VLA-4/fibronectin binding site. Cell 1990; 60: 577-84.