Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
Courtney Premer1, Amarylis Wanschel1, Valeria Porras1
1Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States.
Insights
Stromal-derived factor-1α (SDF-1α) may modulate mesenchymal stem cell (MSC) therapy for dilated cardiomyopathy (DCM). Higher SDF-1α levels correlate with fewer endothelial progenitor cells, suggesting a role in treatment efficacy.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Stem Cell Biology
Background:
- Endothelial dysfunction is central to dilated cardiomyopathy (DCM) pathophysiology.
- Allogeneic, but not autologous, mesenchymal stem cells (MSCs) enhance endothelial function in DCM patients.
- Stromal-derived factor-1α (SDF-1α) release is hypothesized to mediate these MSC effects.
Purpose of the Study:
- To investigate the role of SDF-1α in modulating mesenchymal stem cell (MSC) therapy for dilated cardiomyopathy (DCM).
- To assess the correlation between SDF-1α levels, endothelial progenitor cell (EPC) function, and TNFα in DCM patients treated with MSCs.
Main Methods:
- Assessed plasma TNFα and EPC-colony forming units (EPC-CFUs) in DCM patients receiving autologous or allogeneic MSCs.
- Measured SDF-1α secretion by MSCs and TNFα mRNA expression in endothelial cells (ECs) in vitro.
- Evaluated reactive oxygen species (ROS) generation in ECs in response to SDF-1α.
Main Results:
- Allogeneic MSCs improved EPC-CFUs and decreased plasma TNFα, while autologous MSCs increased TNFα.
- Autologous MSCs secreted significantly higher SDF-1α levels than allogeneic MSCs.
- SDF-1α and TNFα negatively correlated with EPC-CFUs; low-concentration SDF-1α inhibited ROS generation in ECs.
Conclusions:
- MSC-derived SDF-1α secretion inversely correlates with EPC-CFU production in DCM patients.
- SDF-1α may be a key modulator of MSC therapeutic efficacy in dilated cardiomyopathy.
- Findings highlight SDF-1α as a potential biomarker for MSC treatment response in DCM.
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-1α (SDF-1α).
Methods:
Plasma 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.
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 (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.
Conclusion:
MSC 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 Registration:
https://clinicaltrials.gov/ct2/show/NCT01392625, identifier NCT01392625.
