Differentiated mesenchymal stem cells ameliorate cardiovascular complications in diabetic rats
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Cardiovascular manifestations are one of the major complications of type 1 diabetes mellitus (T1DM) and supersede the slow progression of DM in most cases as the leading cause of mortality. There have been many studies and trials in regenerating the functional β-cells of islets from mesenchymal stem cells (MSCs) with varied success. The effect of MSCs ex vivo differentiated to mimic functional insulin-secreting β-cells of islets and their impact on restoration of diabetic complications and transplantation via systemic delivery have not been well studied. In the current study, bone marrow MSCs differentiated to insulin-secreting β-cells are used to treat STZ-induced diabetic rats. The post-homing effects of the differentiated MSCs (dMSCs) were endogenous with definite reversal of diabetic parameters. Consequently, the altered cardiac functions like heart beat rate, left ventricular performance, contractility index and physiological body weight gain due to hyperglycemia were amelorated into normacy. The primary onset cardiac perfomance and the endothelial activation were well evidenced by high fibrinogen levels and systolic blood pressure (SBP) being reversed on the treatment by dMSCs. Further high basal [Ca2+]c in isolated endothelial cells and thereby increased ROS confirmed the endothelial activation. The levels of pro-apoptotic makers p53 and Bax were highly expressed in the diabetic groups indicating oxidative stress through ROS induced by high cytosolic calcium skewing the cells towards apoptosis. The expression of the anti-apoptotic marker Bcl-2 was observed to be low in the diabetic group further augmenting the stress state of endothelial cells (ECs) in T1DM. Restoration of [Ca2+]c chelates ROS and the subsequent reversal of pro- and anti-apoptotic markers after the successful treatment of dMSCs proved that endogenous reconstitution of insulin secretion improves diabetic-induced cardiac manifestations.
KeywordsDiabetic cardiomyopathy STZ Differentiated mesenchymal stem cells Systemic delivery of differentiated cells β-cell regeneration
We thank Muniswamy Madesh, Center for Translational Medicine, Temple University, Philadelphia, USA for confocal micorscopy help. We extend our gratitude to Refaat El-Najar, electron microscopy unit, KKU and Mahmoud Ahmad AL- Khateeb, Department of Physiology, KKU, for help in histology work. This work was supported by internal funds from the Center for Stem Cell Research and the Department of Physiology, King Khalid University.
M.H., M.A.Y. and H.C.C. designed the project. M.H., A.A., M.A.Y., M.M., E.A.M.S and H.C.C. performed the experimental work and analyzed the results. M.H., M.A.Y., M.M. A.A.H and H.C.C. contributed reagents. H.C.C., M.H. and A.A. wrote the manuscript. Experimental work was carried out in the Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt and the Center for Stem Cell Research, College of Medicine, King Khalid University, Abha SA. All authors discussed the results and commented on the manuscript.
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