Dataset Information

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

ABSTRACT: 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? (SDF-1?). Methods:Plasma TNF? 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? secretion by MSCs, endothelial cell (EC) TNF? mRNA expression, and levels of reactive oxygen species (ROS) in response to SDF-1? 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 (?10 ± 4). DCM patients had elevated baseline plasma TNF? (n = 15, 22 ± 9.4 pg/mL). Allogeneic MSCs (n = 8) decreased, and autologous MSCs (n = 7) increased, plasma TNF? (-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? 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? and plasma TNF? negatively correlated with EPC-CFUs in both treatment groups (R = -0.7, P = 0.0004). ECs treated with 20 ng SDF-1? expressed lower levels of TNF? mRNA than cells treated with 100 ng (0.7 ± 0.2 vs. 2.1 ± 0.3, P = 0.0008). SDF-1? at low but not high concentration inhibited the generation of ROS. Conclusion:MSC secretion of SDF-1? 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.

SUBMITTER: Premer C

PROVIDER: S-EPMC6769040 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

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

Premer Courtney C Wanschel Amarylis A Porras Valeria V Balkan Wayne W Legendre-Hyldig Tatiana T Saltzman Russell G RG Dong Chunming C Schulman Ivonne Hernandez IH Hare Joshua M JM

Frontiers in physiology 20190924

<h4>Background</h4>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).<h4>Methods</h4>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 th ...[more]

PMID: 31616309

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Project description:Recent studies have noted the tumor-stroma interaction as an integral part of tumor growth and spread as well as novel avenues for effective treatment. However, the details by which tumor and stroma cells communicate remain poorly understood. Here we show that the migration speed of the non-small-cell lung tumor cell line H838 is significantly increased under the influence of human pulmonary endothelial cells, HPAEC, in a transfilter co-culture system. To elucidate the effect of cell communication on the increased tumor cell migration, we record the H838 transcriptome response after the induction of migration in a hetero- and homogenous co-culture conditions. Gene Set enrichment analysis indicates a migration response of H838 in heterogenous co-culture system. Moreover, computationally transcription factor analysis relates the specific gene expression response to the cytokine-induced up-stream receptor activity and subsequently linking these factors to the upstream receptors via shortest paths across a directed protein-protein interaction network. This analysis predicted TNF- and SDF-1 signaling as well as multiple receptors upstream of Stat3 as putative mediators of the transcriptome response. To close the signaling information path from transcription factors to the possible receptor activation, we determine secretome quantification using a cytokine array. The latter revealed the predicted TNFa, SDF-1a signaling molecules as well as other known migration cytokines, like IL8 and IL6, as possible candidates for increased migration. Addition through the recombinant proteins or respected inhibitions reveal TNFa as well as SDF-1a as an immediate and early-late secreted factors that cause the increase in H838 migration. Interestingly, both factors were not regulated on the gene level of the H838 in heterogenous co-culture conditions, consequential HPAEC produce TNFa and SDF1a as shown by qPCR technique. Concluding, our combined computational and experimental approach revealed a holistic overview on the migration enhancement of lung tumor cells due to endothelial derived factors. Increase in migration is caused by an early TNFa induced inflammation response followed by a SDF-1a activity to sustaining the phenotype of migration. This tumor-endothelial-communication give a new insight for tumor migration.

Dataset Information

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

Publications

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

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