Scientific article
Open access

Impact of syndecan-2-selected mesenchymal stromal cells on the early onset of diabetic cardiomyopathy in diabetic db/db mice

Published inFrontiers in cardiovascular medicine, vol. 8, 632728
Publication date2021
First online date2021-05-21

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.

  • Angiogenesis
  • Cardiac fibrosis
  • Cardiomyocyte stiffness
  • Diabetic cardiomyopathy
  • Immunomodulation
  • Syndecan-2/CD362+-selected stromal cells
  • Type 2 diabetes
  • European 7th Framework - Consortium REDDSTAR [Grant: HEALTH.2012.2.4.3-1]
Citation (ISO format)
PAPPRITZ, Kathleen et al. Impact of syndecan-2-selected mesenchymal stromal cells on the early onset of diabetic cardiomyopathy in diabetic db/db mice. In: Frontiers in cardiovascular medicine, 2021, vol. 8, p. 632728. doi: 10.3389/fcvm.2021.632728
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ISSN of the journal2297-055X

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