Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice
Creators: name: Pappritz, Kathleen
name: Dong, Fengquan
name: Miteva, Kapka
name: Kovacs, Arpad
name: El-Shafeey, Muhammad
name: Kerim, Bahtiyar
name: O'Flynn, Lisa
name: Elliman, Stephen Joseph
name: O'Brien, Timothy
name: Hamdani, Nazha
name: Tschöpe, Carsten
name: Linthout, Sophie Van
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2021
Subjects: subject: type 2 diabetes
subject: diabetic cardiomyopathy
subject: syndecan-2/CD362(+)-selected stromal cells
subject: immunomodulation
subject: cardiomyocyte stiffness
subject: cardiac fibrosis
subject: angiogenesis
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

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 x 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.