Abstract
Endothelial dysfunction is central to the pathophysiology of heart failure, including dilated cardiomyopathy (DCM). Current drug therapies are unable to halt the progression of DCM, compelling the emergence of novel stem cell therapy approaches. Mesenchymal stem cells (MSCs) are pro-angiogenic, immunomodulatory, antifibrotic, and stimulate endogenous endothelial progenitor (EPC) proliferation and function, thus having the potential to ameliorate endothelial dysfunction. We demonstrated that patients with DCM who received allogeneic MSCs had a significant improvement in endothelial function 3-months post treatment, whereas patients who received autologous MSCs had no improvement. Therefore, we hypothesized that allogeneic MSCs preferentially improve endothelial function via a mechanism involving the suppression of pathologic levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 alpha (SDF-1α), and tumor necrosis factor alpha (TNFα). Accordingly, patient serum VEGF and TNFα were measured at baseline and 3 months post MSC treatment. In vitro, MSC secretion of SDF-1α and TNFα was also measured. Our results show that patients with DCM had elevated levels of VEGF (n=21, 581.2±812.2 pg/mL) and TNFα (n=15, 22±9.4 pg/mL) at baseline, and that only allogeneic MSCs were able to restore these levels toward normal (VEGF: n=10, Δ-267.1±252.1, P=0.01; TNFα: n=8, Δ-7.1±3.1 pg/mL, P=0.0005). While there was no difference in TNFα secretion by autologous or allogeneic MSCs (0.01±0.14 vs. 0.4±0.6 pg/mL), autologous MSCs secreted significantly higher levels of SDF-1α compared to allogeneic MSCs (n=12, 79.3±16.7 vs. 14.2±9.4 pg/mL, P=0.0001). In vitro secreted SDF-1α and serum VEGF and TNFα levels correlated with EPC bioactivity (ΔSDF-1α to ΔEPC-CFUs, R=-0.9, P<0.0001; ΔVEGF to ΔEPC-CFUs, R=-0.7, P=0.001; ΔTNFα to ΔEPC-CFUs, R=-0.6, P=0.01). These findings reveal a novel mechanism by which allogeneic MSCs secrete physiologic levels of SDF-1α resulting in physiologic levels of VEGF signaling, reduced TNFα, increased EPC bioactivity, and improved endothelial function. These findings have important clinical and biological implications for the use of MSCs in patients with DCM.