Autologous Culture-Modified Mononuclear Cells Confer Vascular Protection After Arterial Injury

Abstract

Background-Bone marrow-derived cells have been shown to contribute to endothelial replacement after vascular injury.In vitro culture of peripheral blood mononuclear cells produces cells with phenotypic characteristics of endothelium. To test the hypothesis that delivery of autologous culture-modified mononuclear cells (CMMCs) to injured arteries could attenuate the vascular response to injury, a rabbit model was studied. Methods and Results-Rabbit peripheral blood mononuclear cells were cultured in endothelial growth media for 7 to 12 days, yielding highly proliferative cells with distinct endothelial phenotype (expressing CD31 and endothelial nitric oxide synthase and capable of acetylated LDL uptake). A rabbit model of balloon carotid injury was used to evaluate the effect of day 7 CMMC delivery on vascular responses. Animals underwent balloon injury and immediate delivery of autologous CMMCs or buffered saline by 20 minutes of local dwelling. Fluorescence-labeled CMMCs were detected in all vessel layers 4 weeks after delivery. Colonies of cells that localized to the lumen and stained for endothelial markers were also identified. Local CMMC administration at the time of balloon injury accelerated reendothelialization at 4 weeks compared with saline (PϽ0.05). Moreover, CMMC delivery markedly improved endothelium-dependent vasoreactivity at 4 weeks compared with saline (PϽ0.005). Finally, CMMC treatment reduced neointimal formation by 55% at 4 weeks (PϽ0.05). Conclusions-These data demonstrate that delivery of CMMCs to balloon-injured arteries is associated with accelerated reendothelialization, enhanced endothelium-dependent vasoreactivity, and reduced neointimal formation. Thus, delivery of autologous CMMCs represents a novel vasculoprotective approach to attenuate the response to acute vascular injury.

Endothelial Function

“…Interestingly, the repair of vascular injury with EPCs is associated with normalization of endothelial function at the site of the injury. 5 Conversely, the repair of vascular injury may be impaired in the setting of endothelial dysfunction, which may be attributed to 2 possible mechanisms. A recent study demonstrated that the degree of endothelial dysfunction correlated with the number of EPCs.…”

Endothelial progenitor cells: Implications for cardiovascular disease

“…However, the origin of the double-positive EPCs is still under debate. It could be demonstrated by Gulati et al that the vast majority of EPCs arose from a CD14 pos subpopulation of peripheral blood cells, whereas late outgrowth endothelial cells develop exclusively from the CD14 neg fraction (32). Nevertheless, with respect to the characteristics and functional properties Urbich et al reported that adherent cells derived from CD14 pos or CD14 neg MNCs show equal expression of endothelial marker proteins and capacity for clonal expansion (17).…”

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

“…[13][14][15][16][17][22][23][24]81,[97][98][99][100] Autologous EPC transplantation may be used to promote rapid re-endothelialization and restoration of homeostasis in blood vessels injured during revascularization procedures 22-24,97-100 or for seeding of prosthetic grafts, stents, or engineered blood vessels to create a bioactive endothelial layer. 22,23,97,98 We showed recently that transplantation of autologous PB-EPCs leads to rapid re-endothelialization of balloon-denuded rabbit carotid arteries, resulting in significant reduction of neointimal hyperplasia. 23 Using a similar approach, Gulati et al 98 reported that transplantation of cultured autologous MNCs at the time of injury markedly reduced neointima hyperplasia in association with rapid re-endothelization of the damaged vessel.…”

“…22,23,97,98 We showed recently that transplantation of autologous PB-EPCs leads to rapid re-endothelialization of balloon-denuded rabbit carotid arteries, resulting in significant reduction of neointimal hyperplasia. 23 Using a similar approach, Gulati et al 98 reported that transplantation of cultured autologous MNCs at the time of injury markedly reduced neointima hyperplasia in association with rapid re-endothelization of the damaged vessel. Oth- ers have shown the ability of transplanted EPCs to restore endothelial function in damaged vessels.…”