Recent evidence suggests that vascular endothelial cells (EC) and smooth muscle cells (SMC) can develop from circulating bone marrow-derived vascular progenitor cells (VPCs), accumulate at sites of vascular injury, and play a role in both normal vessel healing and pathologic processes such as atherosclerosis. This raises the possibility that VPCs could be used as a cell-based therapy for the treatment of atherosclerosis. Consistent with this, we find that progression of atherosclerosis in ApoE deficient mice can be prevented by the chronic infusion of congenic bone marrow cells, even when the underlying genetic defect is not corrected. Although such findings are intriguing, a direct requirement for vascular progenitor cells in promoting or retarding the development of atherosclerosis has never been demonstrated and other bone marrow-derived cell types, primarily leukocytes, have been suggested to play a role in this process. For this reason, the identity of the bone marrow-derived cell type(s) that actually influence the development of atherosclerosis remains a major unanswered question in this line of research. Here, we will determine the contribution of newly-recruited precursors for four major cell types to the development and modulation of atherosclerosis by using models in which specific lineages of bone marrow-derived cells either fail to develop or can be ablated. These cell types include: endothelial cells, smooth muscle cells, lymphocytes, and dendritic cells.
Our specific aims are: 1. To determine if progenitors of vascular endothelial cells, smooth muscle cells, lymphocytes, or dendritic cells contribute to the inhibition of atherosclerosis after bone marrow cell transfer. 2. To determine if progenitors of vascular endothelial cells or smooth muscle cells contribute to the development of atherosclerosis. These studies will definitively test the contribution of individual cell lineages for their influence on the progression of atherosclerosis. The finding that a particular cell lineage plays a predominant role in regulating the development of atherosclerosis will have significant implications for the use of stem cell therapy for this disease.
