Abstract 5629: Time Course Analysis of Bone-marrow Derived Progenitor Cell Transdifferentiation During Neointima Formation
Background: Transdifferentiation of bone marrow derived progenitor cells (BMPC) into smooth muscle cells (SMC) was suggested to contribute to vascular remodeling processes. However, the ability of these cells to account for highly differentiated contractile SMC remains elusive. In this study, we examined the time points of accumulation, differentiation and the long term contribution of BMPC compared to locally derived SMC in the process of neointima formation.
Methods and Results: C57BL/6 mice were lethally irradiated and subsequently rescued by bone-marrow transplantation (BMTx) of eGFP+-BM. Arterial remodeling was induced by wire injury of the femoral artery, and vessels were harvested after 3 days, 1, 2, 3, 4, 6 and 16 weeks (n=10 animals per time point). Neointima/media ratio and the number of eGFP+-cells in the vessel wall were quantified. Following a careful analysis using deconvolution analysis of z-image stacks and confocal microscopy, the expression of αSMA in eGFP+-cells occurred to be a very rare event. This was also observed for the co-expression of CD31 in BM-derived cells. Moreover, some cells positive for eGFP and αSMA also expressed monocytic lineage markers like CD68 or CD11b. The number of BM derived cells in the neointima constantly declined at later timepoints, and most of the eGFP+-cells were indeed identified as monocytes/macrophages. At 16 weeks after dilatation, highly differentiated SMC were exclusively derived from GFP negative and thus pre-existing resident cells. In addition to these data, selective prevention of resident vascular cell proliferation by irradiation of mice before BMTx inhibited neointima formation in a dose dependent manner.
Conclusions: The contribution of eGFP+-cells to the cellular compartment of the neointimal lesion is limited to a temporary time period of the inflammatory response to the vascular injury. Hence, BM derived cells contribute to arterial remodeling, but these cells do not transdifferentiate into definitive and highly differentiated SMC.