GDF11 enhances therapeutic functions of mesenchymal stem cells for angiogenesis

The efficacy of stem cell therapy for ischemia repair has been limited by low cell retention rate. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family, which has multiple effects on development, physiology and diseases. The objective of the study is to investigate whether GDF11 could affect the efficacy of stem cell transplantation.

We explored the effects of GDF11 on proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy in vitro and in vivo.

Mouse bone marrow-derived MSCs were transduced with lentiviral vector to overexpress GDF11 (MSC^GDF11). After exposed to hypoxia and serum deprivation for 48 h, MSC^GDF11 were significantly better in viability than control MSCs (MSC^vector). MSC^GDF11 also had higher mobility and better angiogenic paracrine effects. The cytokine antibody array showed more angiogenic cytokines in the conditioned medium of MSC^GDF11 than that of MSC^vector, such as epidermal growth factor, platelet-derived growth factor-BB, placenta growth factor. When MSCs (1 × 10⁶ cells in 50 μl) were injected into ischemic hindlimb of mice after femoral artery ligation, MSC^GDF11 had higher retention rate in the muscle than control MSCs. Injection of MSC^GDF11 resulted in better blood reperfusion and limb salvage than that of control MSCs after 14 days. Significantly more CD31⁺ endothelial cells and α-SMA + smooth muscle cells were detected in the ischemic muscles that received MSC^GDF11. The effects of GDF11 were through activating TGF-β receptor and PI3K/Akt signaling pathway.

Our study demonstrated an essential role of GDF11 in promoting therapeutic functions of MSCs for ischemic diseases by enhancing MSC viability, mobility, and angiogenic paracrine functions.