Abstract
BackgroundEndothelial dysfunction contributes to the pathophysiology of dilated cardiomyopathy (DCM). Allogeneic but not autologous mesenchymal stem cells (MSCs) improve endothelial function in DCM patients. We hypothesized that these effects are modulated by release of stromal derived factor-1α (SDF-1α).MethodsPlasma TNFα and endothelial progenitor cell-colony forming units (EPC-CFUs) were assessed at baseline and 3-months post-injection in a subset of POSEIDON-DCM patients that received autologous (n = 11) or allogeneic (n = 10) MSCs. SDF-1α secretion by MSCs, endothelial cell (EC) TNFα mRNA expression, and levels of reactive oxygen species (ROS) in response to SDF-1α were measured in vitro.ResultsAs previously shown, DCM patients (n = 21) had reduced EPC-CFUs at baseline (3 ± 3), which were restored to normal by allogeneic MSCs 3-months post-treatment (Δ10 ± 4). DCM patients had elevated baseline plasma TNFα (n = 15, 22 ± 9.4 pg/mL). Allogeneic MSCs (n = 8) decreased, and autologous MSCs (n = 7) increased, plasma TNFα (−7.1 ± 3.1 vs. 22.2 ± 17.1 pg/mL, respectively; P = 0.0005). In culture, autologous MSCs (n = 11) secreted higher levels of SDF-1α than allogeneic MSCs (n = 6) [76.0 (63.7, 100.9) vs. 22.8 (7.2, 43.5) pg/mL, P = 0.0002]. SDF-1α and plasma TNFα negatively correlated with EPC-CFUs in both treatment groups (R = −0.7, P = 0.0004). ECs treated with 20 ng SDF-1α expressed lower levels of TNFα mRNA than cells treated with 100 ng (0.7 ± 0.2 vs. 2.1 ± 0.3, P = 0.0008). SDF-1α at low but not high concentration inhibited the generation of ROS.ConclusionMSC secretion of SDF-1α inversely correlates with EPC-CFU production in DCM patients and therefore may be a modulator of MSC therapeutic effect in this clinical setting.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT01392625, identifier NCT01392625.
Highlights
Dilated cardiomyopathy (DCM) is the most prevalent type of non-ischemic cardiomyopathy (Go et al, 2014)
These results suggest that secretion of high levels of stromal derived factor-1α (SDF-1α) impair mesenchymal stem cell therapy (MSC) efficacy, underlying the advantage allogeneic MSCs have relative to autologous cells for treatment of DCM
There was an inverse correlation between the change in plasma tumor necrosis factor alpha (TNFα) and the change in endothelial progenitor cell (EPC) colony formation from baseline to 3months post injection (n = 15) (R = −0.7, P = 0.0004, Pearson Correlation; Figure 1E), highlighting that a positive change in EPC-CFUs post-treatment was associated with a reduction in plasma TNFα. These results suggest that the suppression of TNFα by allogeneic, but not autologous, MSCs plays a role in the mechanism mediating the beneficial effects of allogeneic MSC therapy in patients with DCM
Summary
Dilated cardiomyopathy (DCM) is the most prevalent type of non-ischemic cardiomyopathy (Go et al, 2014). Patients receiving allogeneic MSCs had greater improvements in New York Heart Association (NYHA) functional classification and reduced major acute cardiac events (MACE), and hospitalization rates compared to those receiving autologous MSCs (Mushtaq et al, 2014; Hare et al, 2017). While these results are encouraging and have significant implications for the treatment of DCM, the mechanisms underlying the benefits of allogeneic MSCs require further study. Allogeneic but not autologous mesenchymal stem cells (MSCs) improve endothelial function in DCM patients We hypothesized that these effects are modulated by release of stromal derived factor-1α (SDF-1α)
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