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Tissue engineering of bone: crosstalk between osteoblasts and endothelial cells

PD Dr. Filip Simunovic

Osteoblasts and endothelial cells are in close proximity within the bone compartment. In the context of bone tissue engineering, we have seen that coimplantation of human umbilical vein endothelial cells (HUVECs) and human osteoblasts results in the formation of functional blood vessels and enhanced bone regeneration. Implanted HUVECs do not only contribute to blood vessel formation, but also directly affect various cellular parameters in osteoblasts. For example, osteogenic differentiation of osteoblasts is enhanced by cocultivated HUVECs, as evidenced by increased expression of the early osteogenic marker alkaline phosphatase (ALP) and decreased expression of the platelet-derived growth factor receptor-alpha (PDGFR-alpha) in osteoblasts. These effects are mediated by p38 mitogen-activated protein kinase- (p38-MAPK) dependent post-transcriptional modulation of ALP and PDGFR-alpha mRNA stability, including the 3´-untranslated regions (3´-UTRs) of both mRNAs. Moreover, HUVEC co-cultivation also supported proliferation and cell survival of osteoblasts. On the other hand, osteoblasts provoke complex changes in gene expression patterns in cocultivated HUVECs. By using microarray analysis, we have seen upregulation of genes that can be assigned to the functional clusters: extracellular matrix, cell-matrix interactions and angiogenesis. Interestingly, all of the above mentioned changes in both investigated cell types, osteoblasts and HUVECs, were not mediated by soluble secreted factors but were dependent on direct physical co-cultivation. We found evidence that the above mentioned multifarious effects are mediated by direct heterotypic cell contacts between osteoblasts and HUVECs and partially also by cell type-specific deposition of extracellular matrix components. Individual projects within this research area were supported by the German Research Community (DFG) and the Else Kröner-Fresenius-Foundation.