Mesenchymal Stem Cells-Conditioned Media as a Prospective Therapy For Cardiomyopathy In Type 1 Diabetes

Abstract

Background: Diabetic cardiomyopathy is one of the major macrovascular complications that occur in patients with diabetes mellitus. It is characterized by morphological and functional alterations in the heart especially in the left ventricle (LV). In type 1 diabetes mellitus (T1DM), LV hypertrophy as well as systolic dysfunction occur, where the ejection fraction and fractional shortening values significantly decrease affecting the myocardial contractility. Several pathogenic mechanisms underlying T1DM contribute to collagen accumulation and glycosylated protein deposition, ultimately resulting in fibrosis and cardiac injury. Furthermore, an upregulation in the expression of alpha-smooth muscle actin (α-SMA), fibronectin, and NADPH oxidases have been reported in a diabetic milieu. An increasing body of evidence have shown that mesenchymal stem cells (MSCs) have the potential to enhance cardiac function and ameliorate diabetes-induced cardiac damage and myocardial fibrosis. More importantly, the cardio-protective mechanisms of MSCs are most likely to be attributed to their paracrine effect rather than their differentiation potential. Therefore, it is suggested that conditioned media derived from MSCs may attenuate diabetic cardiomyopathy. Aim: The present study aims to assess the cardio-protective role of MSCs-conditioned media and to investigate the molecular mechanisms by which MSCs-conditioned media exert this protective role. We aim to determine the effect of MSCs conditioned media on cardiac function in Streptozotocin (STZ)-induced type 1 diabetic rats, particularly ejection fraction and fractional shortening. We also aim to investigate the molecular changes in cardiac markers of injury including α-SMA, fibronectin and NADPH oxidase 4, as well as the histological alterations mainly fibrosis. Methods: Sprague-Dawley rats were divided into the following groups: a control group and a Streptozotocin-induced type 1 diabetic group. After 6 weeks from diabetes onset, rats were divided into the following groups: (1) Control; (2) Control with weekly injections of MSCs-conditioned media, (3) Diabetic; (4) Diabetic treated with weekly injections of MSCs-conditioned media. Echocardiography studies were performed at the 8th and 12th week of treatment. After 12 weeks of treatment from diabetes onset, functional, histological, biochemical, and molecular parameters of the heart were assessed. Results: Treatment with MSCs-conditioned medium attenuated cardiac injury in diabetic rats. Protection against diabetic cardiomyopathy imparted by MSCs-conditioned media was denoted by decreased myocardial fibrosis and a decrease in collagen and glycosylated proteins deposition in cardiomyocytes. Intriguingly, treatment with MSCs-conditioned media did not decrease blood glucose levels in type 1 diabetic rats, indicating that the cardio-protective role of MSCs-conditioned media is not attributed to the restoration of normal glucose levels. Furthermore, treatment with MSCs-conditioned media restored ejection fraction and fractional shortening to values similar to controls. Moreover, our results show that MSCs-conditioned media tend to decrease the expression of markers of cardiac injury including α-SMA, fibronectin, as well as nox4.

Conclusion: Our results suggest that MSCs-conditioned media may represent a therapeutic modality for diabetic cardiomyopathy. Further in-depth mechanistic investigations are needed to better understand the paracrine effect of MSCs on the heart and to further elucidate the potential molecular mechanisms of this cardioprotective role.