Abstract
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 × 106 WT, CD362−, or CD362+ MSCs were intravenously (i.v.) injected into 20-week-old diabetic BKS.Cg-m+/+Leprdb/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.
Highlights
Diabetes mellitus is a global health problem, and despite enormous advances in therapy options and patient selfmanagement, over 600 million people worldwide are expected to be affected by 2045 [1]
Since regulation of titin phosphorylation via NO-cyclic guanosine monophosphate (cGMP)-PKG signaling [12] is important for proper diastolic function [14], we measured the levels of myocardial NO and cGMP (Figures 1B,C). db/db mice displayed reduced NO and cGMP levels than did db+/db animals, which correlates with the higher Fpassive values observed in db/db mice
Since impaired vascularization underlies diastolic dysfunction [8, 31] and mesenchymal stromal cells (MSCs) are known for their pro-angiogenic properties [11], we evaluated the impact of WT, CD362−, and CD362+ MSC application on artery and arteriole density in left ventricular (LV) sections of db/db mice (Figure 3)
Summary
Diabetes mellitus is a global health problem, and despite enormous advances in therapy options and patient selfmanagement, over 600 million people worldwide are expected to be affected by 2045 [1]. With respect to cardiac repair, MSCs have been demonstrated to differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells [21], but their cardioprotective effects, including immunomodulatory [22,23,24], anti-fibrotic [17], and pro-angiogenic effects [11] have mainly been attributed to their paracrine actions. This includes the ability of MSCs to restore impaired titin phosphorylation and hereto-related cardiomyocyte stiffness and diastolic dysfunction [11, 25].
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