Growth differentiation factor 11 promotes differentiation of MSCs into endothelial-like cells for angiogenesis

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro-angiogenic activities of MSCs, mouse bone marrow-derived MSCs were engineered to overexpress GDF11 (MSC^GDF11 ) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSC^GDF11 than control MSCs (MSC^Vector ) during differentiation. More tube formation was observed in MSC^GDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSC^GDF11 showed more differentiation into CD31⁺ endothelial-like cells and better pro-angiogenic activity as compared with MSC^Vector . Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular-signal-related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF-β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro-angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ-R/ERK/EIF4E pathway.