Tissue Eng Part A. 2015 Dec 9. [Epub ahead of print]

Angiogenic and Immunomodulatory Properties of Endothelial and Mesenchymal Stem Cells.

Bartaula-Brevik S¹, Pedersen TO², Finne-Wistrand A³, Bolstad AI⁴, Mustafa K⁵.

Abstract

It has been suggested that the effect of implanted cells on the local environment is important when selecting the appropriate cell type for tissue regeneration. Our aim was to compare the local tissue response to implanted human mesenchymal stem cells (MSC) and human umbilical vein endothelial cells (EC). MSC and EC were cultured in poly (L-lactide-co-1,5-dioxepan -2-one) scaffolds for 1 week in a bioreactor system, after which they were implanted subcutaneously in NOD/SCID mice. After 3 weeks, scaffolds were retrieved and the mRNA expression of selected genes involved in hypoxia and inflammation were examined by real-time RT-PCR, and correlated with immunofluorescent staining for corresponding proteins. The Toll-like receptor signalling pathway was examined by superarray hybridization. The expression of 53 angiogenesis related proteins was investigated by a proteome profiler angiogenesis antibody array kit. Vascularization was quantified using immunohistochemistry for CD31. The expression of hypoxia-inducible factors and biomarkers for angiogenesis were more strongly up-regulated in response to implanted EC than to MSC, suggesting a higher sensitivity to low oxygen tension among EC. Hypoxia signalling was increased after implantation of EC compared with MSC, leading to a prolonged acute inflammatory phase that promoted ingrowth of vascular cells and establishment of the circulation. Inflammatory cytokines were also differently expressed at the gene and protein level in the two experimental groups, resulting in altered recruitment of acute and chronic inflammatory cells. The end result of these differences was increased vessel formation within the constructs in the EC group.