Increasingly, cell-based therapy with autologous progenitor populations, such as
endothelial progenitor cells (EPC), are being utilized for treatment of vascular diseases.
However, both the number and functional capacity are diminished when cells are derived
from patients with established risk factors for coronary artery disease (CAD). Herein, we
report that inhibition of glycogen synthase kinase 3 (GSK) can improve both the number
and function of endothelial progenitor cells in patients with CAD or diabetes mellitus
(DM) leading to greater therapeutic benefit. Specifically, use of various small molecule
inhibitors of GSK (GSKi) results in a 4-fold increased number of EPCs. Moreover, GSKi
treatment improves the functional profile of EPCs through reductions in apoptosis,
improvements in cell adhesion through up-regulation of very-late antigen-4 (VLA-4), and by increasing paracrine efficacy by increasing vascular endothelial growth factor (VEGF)secretion. Therapeutic improvement was confirmed in vivo by increased reendothelialization(RE) and reductions of neointima (NI) formation achieved when GSKi-treated cells were administered following vascular injury to CD-1 nude mice. Because cell-based therapy is technically challenging, we also tested a strategy of local delivery of GSKi at the site of arterial injury through GSKi-eluting stents. In vitro, GSKi elution increased EPC attachment to stent struts. In vivo, GSKi-eluting stents deployed in rabbit carotid arteries resulted in systemic mobilization of EPCs, improved local RE, and important reductions in in-stent NI formation. Finally, we tested the ability of GSKi to improve EPC-mediated arterial repair in patients with DM. As in patients with CAD,
GSKi treatment improved EPC yield and diminished in vitro apoptosis. Utilizing a
proteomics approach, we identified Cathepsin B (catB) as a differentially regulated protein necessary for reductions in apoptosis. Indeed, antagonism of catB prevented GSKi improvements in GSKi treated EPC mediated arterial repair in a xenotransplant wire injury model. Thus, our data demonstrates that GSKi treatment results in improvements in EPC number and function in vitro and in vivo resulting in enhanced arterial repair following mechanical injury. Accordingly, GSK antagonism is an effective cell enhancement strategy for autologous cell-based therapy with EPCs from high risk patients such as CAD or DM.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/24348 |
| Date | January 2013 |
| Creators | Hibbert, Benjamin |
| Contributors | O'Brien, Edward |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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