Adipose and cardiac progenitor cells for regenerative medicine

Cardiovascular diseases, and the progression to heart failure, are one of the leading cause of death. Diabetes is often associate with cardiovascular complications because of the disturbed substrate metabolism that can alter the homeostasis of the tissues and modify the progenitor cell populations. Most adult tissues have a mesenchymal progenitor cell subpopulation that represents a proportion of the total cell number and which, because of its regenerative properties, is an attractive source for cell therapy. Recently it has been proved that injection of mesenchymal cells improve contractile function in rodents following myocardial infarction. The aim of this study was to isolate, characterize and differentiate adipose-derived mesenchymal stem cells (ADMSCs), and cardiosphere-derived cells (CDCs), and to determine the effect of simply a high fat diet on these two mesenchymal populations. Cardiac explant-derived and cardiosphere-derived cells (EDCs, CDCs) were cultured from atrial tissue and adipose stem cells were cultured from epididymal fat depots after collagenase digestion. Cultured ADMSCs contained more CD90+ cells (47% vs 87%) and fewer DDR2+ and CD45+ cells compared to freshly isolated ADMSCs (respectively 9% and 20% vs 38% and 42%). Various media were tested to validate the differentiation capacity of adipose mesenchymal cells, but only the TGFβ-supplemented medium was able to increase the expression of cardiac specific genes. Hypoxia increased cell proliferation and changed the surface marker profile of ADMSCs; more DDR2+ cells and fewer CD45+ and CD90+ cells were found compared to normoxic ADMSCs. In vitro expansion of neonatal cardiac fibroblasts and cardiosphere-derived cells revealed a similarity between these two cell populations, both increased proliferation and clonogenic capacity with time in culture and expressed mesenchymal/fibroblast markers such as CD90 and DDR2. CDCs were able to acquire a cardiac phenotype in vitro, increasing gene expression of cardiac actin and troponin T, however no beating cells were observed. After 4 months of high-fat diet (55% fat; HFD,) mice had raised fed plasma glucose, cholesterol and insulin levels and decreased plasma lactate. Significantly more ADMSCs were obtained from high fat fed animals and ADMSC numbers correlated with plasma glucose, cholesterol and lactate. Expression of CD45, DDR2 and CD105 were increased in ADMSCs from high fat fed mice and the functional properties and differentiation capacity were slightly decreased. No differences in surface marker expression and functional properties were detected between high fat and chow diet mice CDCs. In conclusion, four months of HFD induced a diabetic phenotype in C57 Black 6 mice. The high fat diet increased ADMSCs yield but modified the balance of ADMSCs populations and decreased their differentiation capacity. In contrast, cardiac progenitor cells were unaffected by induction of the diabetic phenotype.