Abstract 12017: Contribution of Stem Cells to Neointimal Formation of Decellularized Vessel Grafts in a Novel Mouse Model
Background - Restenosis or neointima formation is a major complication in patients receiving percutaneous coronary intervention, vessel bypass graft or organ transplantation. Despite extensive research, the mechanism of lesional cell accumulation remains unclear and the methods available to slow or prevent its formation continue to be limited.
Methods and Results - To further elucidate and quantify which cell types contribute to the developing neointima, we established a novel mouse model of restenosis, by grafting a decellularized vessel to the carotid artery. Typically, the graft developed neointimal lesions after 2 weeks, resulting in lumen closure within 4 weeks. Although no cells initially existed in the grafted vessel wall, immunohistochemical staining revealed the presence of endothelial and smooth muscle cells, monocytes and stem/progenitor cells 2 weeks post-implantation. Cultured lesional cells expressed a panel of stem/progenitor markers including c-kit, Sca-1 and CD34. Furthermore, they showed clonogenic and multilineage differentiation capacities. Some clones highly expressed mesenchymal stem cell markers, e.g. CD90, CD44, CD105 and vasculogenic progenitor cell markers (Sca-1 and CD34). These cells also displayed the capability of differentiation into adipocytes and osteogenesis. Isolated Sca-1+ cells were able to differentiate into endothelial and smooth muscle cells in response to VEGF or PDGF-BB stimulation in vitro. Studies with bone marrow transplantation from SM22-LacZ transgenic mice showed that bone marrow stem cells did not contribute to the formation of smooth muscle cells in the neointima. In vivo, local application of VEGF to the adventitial side of the decellularized vessel, increased re-endothelialization and reduced neointimal formation in samples at 4 weeks post-implantation.
Conclusions - A population of stem/progenitor cells exists within developing neointima of decellularized vessel grafts in a new mouse model, which display the ability to differentiate into both endothelial and smooth muscle cells and can contribute to restenosis. Our findings also indicate that drugs or cytokines directing cell differentiation toward endothelial lineage may be effective tools in retarding restenosis.
- © 2011 by American Heart Association, Inc.