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Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy

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 (...

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Autores principales: Premer, Courtney, Wanschel, Amarylis, Porras, Valeria, Balkan, Wayne, Legendre-Hyldig, Tatiana, Saltzman, Russell G., Dong, Chunming, Schulman, Ivonne Hernandez, Hare, Joshua M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769040/
https://www.ncbi.nlm.nih.gov/pubmed/31616309
http://dx.doi.org/10.3389/fphys.2019.01182
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author Premer, Courtney
Wanschel, Amarylis
Porras, Valeria
Balkan, Wayne
Legendre-Hyldig, Tatiana
Saltzman, Russell G.
Dong, Chunming
Schulman, Ivonne Hernandez
Hare, Joshua M.
author_facet Premer, Courtney
Wanschel, Amarylis
Porras, Valeria
Balkan, Wayne
Legendre-Hyldig, Tatiana
Saltzman, Russell G.
Dong, Chunming
Schulman, Ivonne Hernandez
Hare, Joshua M.
author_sort Premer, Courtney
collection PubMed
description 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.
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spelling pubmed-67690402019-10-15 Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy Premer, Courtney Wanschel, Amarylis Porras, Valeria Balkan, Wayne Legendre-Hyldig, Tatiana Saltzman, Russell G. Dong, Chunming Schulman, Ivonne Hernandez Hare, Joshua M. Front Physiol Physiology 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. Frontiers Media S.A. 2019-09-24 /pmc/articles/PMC6769040/ /pubmed/31616309 http://dx.doi.org/10.3389/fphys.2019.01182 Text en Copyright © 2019 Premer, Wanschel, Porras, Balkan, Legendre-Hyldig, Saltzman, Dong, Schulman and Hare. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Premer, Courtney
Wanschel, Amarylis
Porras, Valeria
Balkan, Wayne
Legendre-Hyldig, Tatiana
Saltzman, Russell G.
Dong, Chunming
Schulman, Ivonne Hernandez
Hare, Joshua M.
Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
title Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
title_full Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
title_fullStr Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
title_full_unstemmed Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
title_short Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy
title_sort mesenchymal stem cell secretion of sdf-1α modulates endothelial function in dilated cardiomyopathy
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769040/
https://www.ncbi.nlm.nih.gov/pubmed/31616309
http://dx.doi.org/10.3389/fphys.2019.01182
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