期刊
FRONTIERS IN PHYSIOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2019.01182
关键词
endothelial dysfunction; mesenchymal stem cells; allogeneic; dilated cardiomyopathy; SDF 1 alpha
类别
资金
- American Heart Association (AHA) Pre-doctoral Fellowship [15PRE25730025]
- National Institute of Health (NIH) [R01 HL RO0110737]
- NIH [1R01 HL134558, 5UM 1HL113460, R01 HL137355, R01 HL107110]
- Starr Family Foundation
- Soffer Family Foundation
Background: Endothelial 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-1 alpha (SDF-1 alpha). Methods: Plasma TNF alpha 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-1 alpha secretion by MSCs, endothelial cell (EC) TNF alpha mRNA expression, and levels of reactive oxygen species (ROS) in response to SDF-1 alpha were measured in vitro. Results: As 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 (Delta 10 +/- 4). DCM patients had elevated baseline plasma TNF alpha (n = 15, 22 +/- 9.4 pg/mL). Allogeneic MSCs (n = 8) decreased, and autologous MSCs (n = 7) increased, plasma TNF alpha (-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-1 alpha than allogeneic MSCs (n = 6) [76.0 (63.7, 100.9) vs. 22.8 (7.2, 43.5) pg/mL, P = 0.0002]. SDF-1 alpha and plasma TNF alpha negatively correlated with EPC-CFUs in both treatment groups (R = -0.7, P = 0.0004). ECs treated with 20 ng SDF-1 alpha expressed lower levels of TNF alpha mRNA than cells treated with 100 ng (0.7 +/- 0.2 vs. 2.1 +/- 0.3, P = 0.0008). SDF-1 alpha at low but not high concentration inhibited the generation of ROS. Conclusion: MSC secretion of SDF-1 alpha inversely correlates with EPC-CFU production in DCM patients and therefore may be a modulator of MSC therapeutic effect in this clinical setting.
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