title: Collagen matrix-induced expression of integrin αVβ3 in circulating angiogenic cells can be targeted by matricellular protein CCN1 to enhance their function.
abstract: Circulating angiogenic cells (CACs) play an important role in vascular homeostasis and hold therapeutic promise for treating a variety of cardiovascular diseases. However, further improvements are needed because the effects of CAC therapy remain minimal or transient. The regenerative potential of these cells can be improved by culture on a collagen-based matrix through the up-regulation of key integrin proteins. We found that human CAC function was enhanced by using the matricellular protein CCN1 (CYR61/CTGF/NOV family member 1) to target integrin αV and β3, which are up-regulated on matrix. Compared to matrix-cultured CACs, CCN1-matrix CACs exhibited a 2.2-fold increase in cell proliferation, 1.8-fold greater migration toward VEGF, and 1.7-fold more incorporation into capillary-like structures in an angiogenesis assay. In vivo, intramuscular injection of CCN1-matrix-cultured CACs into ischemic hind limbs of CD-1 nude mice resulted in blood flow recovery to 80% of baseline, which was greater than matrix-cultured CACs (66%) and PBS (35%) treatment groups. Furthermore, transplanted CCN1-matrix CACs exhibited greater engraftment (11-fold) and stimulated the up-regulation of survival and angiogenic genes (>3-fold). These findings reveal the importance of cell-matrix interactions in regulating CAC function and also reveal a mechanism by which these may be exploited to enhance cell therapies for ischemic disease.
authors.affiliation: *Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: McNeill
authors.affiliation: *Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Branka
authors.initials: B
authors.lastname: Vulesevic
authors.affiliation: *Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ostojic
authors.affiliation: *Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
authors.affiliation: *Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada esuuronen@ottawaheart.ca.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism*; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D055515:Cysteine-Rich Protein 61; D039302:Integrin alphaVbeta3; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: biomaterial; cardiovascular disease; cell preconditioning; ischemia; neovascularization