The objective of this proposal is to characterize and enhance the vasoprotective effects of culture-modified mononuclear cells (CMMCs) and endothelial outgrowth cells (EOCs) in an animal model of acute vascular injury. Recent studies in chimeric animal models have demonstrated that bone marrow-derived cells participate in the cellular response to vascular injury. Circulating mononuclear cells, cultured in vitro under appropriate conditions, may assume an endothelial phenotype. Our goal is to adapt and modify these autologous cells for therapeutic purposes. CMMCs are generated by culturing peripheral blood mononuclear cells (PBMCs) towards an endothelial phenotype using defined conditions. Following 7 days in culture, the majority of early CMMCs express CD14 (the LPS receptor and a monocyte marker) although this heterogenous population also includes precursors to endothelial outgrowth cells (EOCs) and sloughed mature circulating endothelial cells (both CD14-). At later time points, these cultures consist of homogenous populations of EOCs (CD14-). Work in our laboratory has demonstrated potent vasoprotective effects of locally delivered early CMMCs and EOCs in a model of direct vascular injury. Our first working hypothesis is that autologous early CMMCs and EOCs exert vasoprotective actions in the injured vasculature in an endothelial dependent fashion. Our second working hypothesis is that genetic modification will further enhance the vasoprotective effects of EOCs. Our four specific aims are:
Specific Aim 1 : To compare the vasoprotective effects associated with local delivery of early CMMCs and EOCs.
Specific Aim 2 : To define the mechanisms responsible for the vasoprotective effects of early CMMC and EOC delivery.
Specific Aim 3 : To optimize transgene expression from genetically modified EOCs and to enhance their local vasoprotective actions.
Specific Aim 4 : To optimize systemic transgene expression from genetically modified EOCs and to determine their systemic vasoprotective potential. ? ?
| Psaltis, Peter J; Harbuzariu, Adriana; Delacroix, Sinny et al. (2012) Identification of a monocyte-predisposed hierarchy of hematopoietic progenitor cells in the adventitia of postnatal murine aorta. Circulation 125:592-603 |
| Kiernan, T J; Boilson, B A; Tesmer, L et al. (2011) Effect of enhanced external counterpulsation on circulating CD34+ progenitor cell subsets. Int J Cardiol 153:202-6 |
| Psaltis, Peter J; Harbuzariu, Adriana; Delacroix, Sinny et al. (2011) Resident vascular progenitor cells--diverse origins, phenotype, and function. J Cardiovasc Transl Res 4:161-76 |
| Chade, Alejandro R; Zhu, Xiangyang; Lavi, Ronit et al. (2009) Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation 119:547-57 |
| Kiernan, Thomas J; Boilson, Barry A; Witt, Tyra A et al. (2009) Vasoprotective effects of human CD34+ cells: towards clinical applications. J Transl Med 7:66 |
| Kiernan, Thomas J; Boilson, Barry A; Sandhu, Gurpreet S et al. (2009) Nonrevascularizable coronary artery disease following coronary artery bypass graft surgery: a population-based study in Olmsted County, Minnesota. Coron Artery Dis 20:106-11 |
| Froehlich, Harald; Gulati, Rajiv; Boilson, Barry et al. (2009) Carotid repair using autologous adipose-derived endothelial cells. Stroke 40:1886-91 |
| Boilson, Barry A; Kiernan, Thomas J; Harbuzariu, Adriana et al. (2008) Circulating CD34+ cell subsets in patients with coronary endothelial dysfunction. Nat Clin Pract Cardiovasc Med 5:489-96 |
| Pislaru, Sorin V; Harbuzariu, Adriana; Gulati, Rajiv et al. (2006) Magnetically targeted endothelial cell localization in stented vessels. J Am Coll Cardiol 48:1839-45 |
| Pislaru, Sorin V; Harbuzariu, Adriana; Agarwal, Gautam et al. (2006) Magnetic forces enable rapid endothelialization of synthetic vascular grafts. Circulation 114:I314-8 |
Showing the most recent 10 out of 14 publications
