Growth Differentiation Factor 11 Supports Migration and Sprouting of Endothelial Progenitor Cells

Background: Neovascularization plays an important role in tissue engineering applications. In animal models, it was demonstrated that implantation of endothelial progenitor cells (EPCs) from cord blood led to the formation of a complex functional neovasculature, whereas EPCs isolated from peripheral blood (pbEPCs) showed a limited vasculogenic potential, which may be attributed to age-related dysfunction. Growth differentiation factor 11 (GDF11) was recently identified as a rejuvenation factor, which was able to reverse age-related dysfunction of stem cells. Therefore, we hypothesized that GDF11 may improve the vasculogenesis-related phenotype of pbEPCs.

Materials And Methods: pbEPCs were isolated from adult peripheral blood. Transforming growth factor (TGF)-β type-I receptor expression was analyzed by immunostaining. pbEPCs were treated with recombinant GDF11 for various time periods. Thereafter, phosphorylation of Smad2/Smad3, adhesion, proliferation, cell survival, migration, and in vitro sprout formation was investigated.

Results: pbEPCs express the TGF-β type-I receptors ALK4 and ALK5, but not ALK7. Treatment of pbEPCs with recombinant GDF11 resulted in activation of the Smad2/Smad3 pathway and in increased migration, which was inhibited by the TGF-β1 superfamily type-I activin receptor-like kinase inhibitor SB431542, demonstrating that the TGF-β receptor-Smad2/Smad3 pathway is involved in GDF11 induced migration. Moreover, in vitro sprout formation was increased as well by GDF11 treatment. However, other parameters such as adherence, proliferation, and apoptosis were not affected by GDF11.

Conclusions: This study provides evidence that GDF11 improves vasculogenesis-related growth parameters in pbEPCs and may represent a therapeutic option to ameliorate the angiogenic and vasculogenic properties of pbEPCs.