VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes
Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditi...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-01-01
|
| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2021/8888575 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850177403748352000 |
|---|---|
| author | Denise Philipp Michelle Holthaus Vida Basoah Kurt Pfannkuche Laura Suhr Thorsten Wahlers Adnana Paunel-Görgülü |
| author_facet | Denise Philipp Michelle Holthaus Vida Basoah Kurt Pfannkuche Laura Suhr Thorsten Wahlers Adnana Paunel-Görgülü |
| author_sort | Denise Philipp |
| collection | DOAJ |
| description | Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis. |
| format | Article |
| id | doaj-art-bf2483d5b37744deaccb6c6fef9bdfd3 |
| institution | OA Journals |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-bf2483d5b37744deaccb6c6fef9bdfd32025-08-20T02:18:58ZengWileyStem Cells International1687-966X1687-96782021-01-01202110.1155/2021/88885758888575VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived CardiomyocytesDenise Philipp0Michelle Holthaus1Vida Basoah2Kurt Pfannkuche3Laura Suhr4Thorsten Wahlers5Adnana Paunel-Görgülü6Department of Cardiothoracic Surgery, Heart Center of the University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center of the University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center of the University of Cologne, Cologne, GermanyCenter for Physiology and Pathophysiology, Institute for Neurophysiology, University of Cologne, Medical Faculty, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center of the University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center of the University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center of the University of Cologne, Cologne, GermanyMyocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis.http://dx.doi.org/10.1155/2021/8888575 |
| spellingShingle | Denise Philipp Michelle Holthaus Vida Basoah Kurt Pfannkuche Laura Suhr Thorsten Wahlers Adnana Paunel-Görgülü VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes Stem Cells International |
| title | VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes |
| title_full | VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes |
| title_fullStr | VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes |
| title_full_unstemmed | VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes |
| title_short | VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes |
| title_sort | vegf contributes to mesenchymal stem cell mediated reversion of nor1 dependent hypertrophy in ips cell derived cardiomyocytes |
| url | http://dx.doi.org/10.1155/2021/8888575 |
| work_keys_str_mv | AT denisephilipp vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes AT michelleholthaus vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes AT vidabasoah vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes AT kurtpfannkuche vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes AT laurasuhr vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes AT thorstenwahlers vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes AT adnanapaunelgorgulu vegfcontributestomesenchymalstemcellmediatedreversionofnor1dependenthypertrophyinipscellderivedcardiomyocytes |