Abstract 16025: Macrophages are Critical determinants of Vascular Progenitor Cell Lineage Differentiation Through TNF-α Mediated Canonical NF-κB Activation
Background - Recent data indicates the existence of a population of tissue-resident progenitors that can give rise to cells of both the endothelial and smooth muscle lineages. Macrophages have been established as key inflammatory cells that can promote atherosclerotic plaque progression.
Methods and Results - Here we examined the ability of macrophages to directly regulate progenitor differentiation in vitro and in vivo. Either murine adult vascular progenitor cells derived from vessel wall or embryonic stem cells were cultured with the peritoneal macrophages or cell line J774A. Analysis of gene and protein expression with endothelial-specific markers (CD31, CD144, eNOS and Flk-1) indicated the profound capacity of the macrophages to induce endothelial differentiation from the stem/progenitor cells. In vivo Matrigel plug assay indicated the endothelial cell-like phenotype derived from stem cells in the presence of macrophages. Interestingly, macrophages could promote the simultaneous suppression of stem/progenitor cell differentiation towards the smooth muscle lineage. Further analysis revealed that both the induction of endothelial cell and inhibition of smooth muscle differentiation were mediated by macrophage-derived TNF-alpha via TNF-alpha receptor 1 and specific activation of the canonical NF-κB signalling pathways. The over-expression of NF-κB (p65) similarly enhanced endothelial differentiation whereas NF-κB (p65) or TNF-alpha receptor 1 knockdown led to a significant decrease in TNF-alpha mediated-endothelial differentiation. Consistently, ex vivo experiments using a decellularised vessel system indicated both an increase in the number of endothelial cells as well as a reduction in smooth muscle marker expression in the presence of TNF-alpha. Functionally, knockout of TNF-alpha resulted in significant reduction of neointimal lesions in vein grafts of mice, which coincided with decreased angiogenesis within the grafts.
Conclusion - These data provide the first evidence that macrophages are key players in controlling the lineage commitment of vascular stem/progenitor cells in vitro and in vivo, in which TNF-alpha/TNFR1/NFκB signal pathways are crucial.
- © 2012 by American Heart Association, Inc.