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Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice
Background: Mesenchymal stromal cells (MSCs) are an attractive cell type for cell therapy given their immunomodulatory, anti-fibrotic, and endothelial-protective features. The heparin sulfate proteoglycan, syndecan-2/CD362, has been identified as a functional marker for MSC isolation, allowing one t...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175674/ https://www.ncbi.nlm.nih.gov/pubmed/34095245 http://dx.doi.org/10.3389/fcvm.2021.632728 |
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author | Pappritz, Kathleen Dong, Fengquan Miteva, Kapka Kovacs, Arpad El-Shafeey, Muhammad Kerim, Bahtiyar O'Flynn, Lisa Elliman, Stephen Joseph O'Brien, Timothy Hamdani, Nazha Tschöpe, Carsten Van Linthout, Sophie |
author_facet | Pappritz, Kathleen Dong, Fengquan Miteva, Kapka Kovacs, Arpad El-Shafeey, Muhammad Kerim, Bahtiyar O'Flynn, Lisa Elliman, Stephen Joseph O'Brien, Timothy Hamdani, Nazha Tschöpe, Carsten Van Linthout, Sophie |
author_sort | Pappritz, Kathleen |
collection | PubMed |
description | Background: Mesenchymal stromal cells (MSCs) are an attractive cell type for cell therapy given their immunomodulatory, anti-fibrotic, and endothelial-protective features. The heparin sulfate proteoglycan, syndecan-2/CD362, has been identified as a functional marker for MSC isolation, allowing one to obtain a homogeneous cell product that meets regulatory requirements for clinical use. We previously assessed the impact of wild-type (WT), CD362(−), and CD362(+) MSCs on local changes in protein distribution in left ventricular (LV) tissue and on LV function in an experimental model of early-onset diabetic cardiomyopathy. The present study aimed to further explore their impact on mechanisms underlying diastolic dysfunction in this model. Materials: For this purpose, 1 × 10(6) WT, CD362(−), or CD362(+) MSCs were intravenously (i.v.) injected into 20-week-old diabetic BKS.Cg-m+/+Lepr(db)/BomTac, i.e., db/db mice. Control animals (db+/db) were injected with the equivalent volume of phosphate-buffered saline (PBS) alone. After 4 weeks, mice were sacrificed for further analysis. Results: Treatment with all three MSC populations had no impact on blood glucose levels in db/db mice. WT, CD362(−), and CD362(+) MSC application restored LV nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) levels in db/db mice, which correlated with a reduction in cardiomyocyte stiffness. Furthermore, all stromal cells were able to increase arteriole density in db/db mice. The effect of CD362(+) MSCs on NO and cGMP levels, cardiomyocyte stiffness, and arteriole density was less pronounced than in mice treated with WT or CD362(−) MSCs. Analysis of collagen I and III protein expression revealed that fibrosis had not yet developed at this stage of experimental diabetic cardiomyopathy. All MSCs reduced the number of cardiac CD3(+) and CD68(+) cells in db/db mice, whereas only splenocytes from CD362(−)- and CD362(+)-db/db mice exhibited a lower pro-fibrotic potential compared to splenocytes from db/db mice. Conclusion: CD362(+) MSC application decreased cardiomyocyte stiffness, increased myocardial NO and cGMP levels, and increased arteriole density, although to a lesser extent than WT and CD362(−) MSCs in an experimental model of early-onset diabetic cardiomyopathy without cardiac fibrosis. These findings suggest that the degree in improvement of cardiomyocyte stiffness following CD362(+) MSC application was insufficient to improve diastolic function. |
format | Online Article Text |
id | pubmed-8175674 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81756742021-06-05 Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice Pappritz, Kathleen Dong, Fengquan Miteva, Kapka Kovacs, Arpad El-Shafeey, Muhammad Kerim, Bahtiyar O'Flynn, Lisa Elliman, Stephen Joseph O'Brien, Timothy Hamdani, Nazha Tschöpe, Carsten Van Linthout, Sophie Front Cardiovasc Med Cardiovascular Medicine Background: Mesenchymal stromal cells (MSCs) are an attractive cell type for cell therapy given their immunomodulatory, anti-fibrotic, and endothelial-protective features. The heparin sulfate proteoglycan, syndecan-2/CD362, has been identified as a functional marker for MSC isolation, allowing one to obtain a homogeneous cell product that meets regulatory requirements for clinical use. We previously assessed the impact of wild-type (WT), CD362(−), and CD362(+) MSCs on local changes in protein distribution in left ventricular (LV) tissue and on LV function in an experimental model of early-onset diabetic cardiomyopathy. The present study aimed to further explore their impact on mechanisms underlying diastolic dysfunction in this model. Materials: For this purpose, 1 × 10(6) WT, CD362(−), or CD362(+) MSCs were intravenously (i.v.) injected into 20-week-old diabetic BKS.Cg-m+/+Lepr(db)/BomTac, i.e., db/db mice. Control animals (db+/db) were injected with the equivalent volume of phosphate-buffered saline (PBS) alone. After 4 weeks, mice were sacrificed for further analysis. Results: Treatment with all three MSC populations had no impact on blood glucose levels in db/db mice. WT, CD362(−), and CD362(+) MSC application restored LV nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) levels in db/db mice, which correlated with a reduction in cardiomyocyte stiffness. Furthermore, all stromal cells were able to increase arteriole density in db/db mice. The effect of CD362(+) MSCs on NO and cGMP levels, cardiomyocyte stiffness, and arteriole density was less pronounced than in mice treated with WT or CD362(−) MSCs. Analysis of collagen I and III protein expression revealed that fibrosis had not yet developed at this stage of experimental diabetic cardiomyopathy. All MSCs reduced the number of cardiac CD3(+) and CD68(+) cells in db/db mice, whereas only splenocytes from CD362(−)- and CD362(+)-db/db mice exhibited a lower pro-fibrotic potential compared to splenocytes from db/db mice. Conclusion: CD362(+) MSC application decreased cardiomyocyte stiffness, increased myocardial NO and cGMP levels, and increased arteriole density, although to a lesser extent than WT and CD362(−) MSCs in an experimental model of early-onset diabetic cardiomyopathy without cardiac fibrosis. These findings suggest that the degree in improvement of cardiomyocyte stiffness following CD362(+) MSC application was insufficient to improve diastolic function. Frontiers Media S.A. 2021-05-21 /pmc/articles/PMC8175674/ /pubmed/34095245 http://dx.doi.org/10.3389/fcvm.2021.632728 Text en Copyright © 2021 Pappritz, Dong, Miteva, Kovacs, El-Shafeey, Kerim, O'Flynn, Elliman, O'Brien, Hamdani, Tschöpe and Van Linthout. https://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 | Cardiovascular Medicine Pappritz, Kathleen Dong, Fengquan Miteva, Kapka Kovacs, Arpad El-Shafeey, Muhammad Kerim, Bahtiyar O'Flynn, Lisa Elliman, Stephen Joseph O'Brien, Timothy Hamdani, Nazha Tschöpe, Carsten Van Linthout, Sophie Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice |
title | Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice |
title_full | Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice |
title_fullStr | Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice |
title_full_unstemmed | Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice |
title_short | Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice |
title_sort | impact of syndecan-2-selected mesenchymal stromal cells on the early onset of diabetic cardiomyopathy in diabetic db/db mice |
topic | Cardiovascular Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175674/ https://www.ncbi.nlm.nih.gov/pubmed/34095245 http://dx.doi.org/10.3389/fcvm.2021.632728 |
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