Placenta-Derived Adherent Stromal Cells Improve Diabetes Mellitus-Associated Left Ventricular Diastolic Performance.
Sophie Van LinthoutNazha HamdaniKapka MitevaAnnika KoschelIrene MüllerLena PinzurZami AbermanKathleen PappritzWolfgang Albrecht LinkeCarsten TschöpePublished in: Stem cells translational medicine (2017)
Left ventricular (LV) diastolic dysfunction is among others attributed to cardiomyocyte stiffness. Mesenchymal stromal cells (MSC) have cardiac-protective properties. We explored whether intravenous (i.v.) application of PLacenta-eXpanded (PLX) MSC-like cells (PLX) improves LV diastolic relaxation in streptozotocin (STZ)-induced diabetic mice and investigated underlying mechanisms. Diabetes mellitus was induced by STZ application (50 mg/kg body weight) during five subsequent days. One week after the first STZ injection, PLX or saline were i.v. applied. Two weeks later, mice were hemodynamically characterized and sacrificed. At this early stage of diabetic cardiomyopathy with low-grade inflammation and no cardiac fibrosis, PLX reduced LV vascular cell adhesion molecule-1, transforming growth factor-β1, and interferon-γ mRNA expression, induced the percentage of circulating regulatory T cells, and decreased the splenic pro-fibrotic potential in STZ mice. STZ + PLX mice exhibited higher LV vascular endothelial growth factor mRNA expression and arteriole density versus STZ mice. In vitro, hyperglycemic PLX conditioned medium restored the hyperglycemia-impaired tube formation and adhesion capacity of human umbelical vein endothelial cells (HUVEC) via increasing nitric oxide (NO) bioavailability. PLX further induced the diabetes-downregulated activity of the NO downstream protein kinase G, as well as of protein kinase A, in STZ mice, which was associated with a raise in phosphorylation of the titin isoforms N2BA and N2B. Concomitantly, the passive force was lower in single isolated cardiomyocytes from STZ + PLX versus from STZ mice, which led to an improvement of LV diastolic relaxation. We conclude that i.v. PLX injection improves diabetes mellitus-associated diastolic performance via decreasing cardiomyocyte stiffness. Stem Cells Translational Medicine 2017;6:2135-2145.
Keyphrases
- diabetic rats
- left ventricular
- oxidative stress
- endothelial cells
- high glucose
- low grade
- high fat diet induced
- heart failure
- blood pressure
- protein kinase
- stem cells
- nitric oxide
- vascular endothelial growth factor
- early stage
- regulatory t cells
- acute myocardial infarction
- body weight
- transforming growth factor
- cardiac resynchronization therapy
- aortic stenosis
- left atrial
- mitral valve
- high grade
- dendritic cells
- type diabetes
- ejection fraction
- hypertrophic cardiomyopathy
- bone marrow
- low dose
- acute coronary syndrome
- mesenchymal stem cells
- angiotensin ii
- lymph node
- cardiovascular disease
- metabolic syndrome
- risk assessment
- insulin resistance
- escherichia coli
- glycemic control
- idiopathic pulmonary fibrosis
- immune response
- cell adhesion
- aortic valve
- radiation therapy
- transcatheter aortic valve replacement
- mass spectrometry
- candida albicans
- anti inflammatory
- cystic fibrosis
- high resolution
- cell therapy