Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

AbstractAlthough cell therapy improves cardiac function after myocardial infarction, highly variable results and limited understanding of the underlying mechanisms preclude its clinical translation. Because many heart failure patients are diabetic, we examined how diabetic conditions affect the characteristics of cardiac mesenchymal cells (CMC) and their ability to promote myocardial repair in mice. To examine how diabetes affects CMC function, we isolated CMCs from non-diabetic C57BL/6J (CMCWT) or diabetic B6.BKS(D)-Leprdb/J (CMCdb/db) mice. When CMCs were grown in 17.5  mM glucose, CMCdb/db cells showed>  twofold higher glycolytic activity and a threefold higher expression ofPfkfb3 compared with CMCWT cells; however, culture of CMCdb/db cells in 5.5  mM glucose led to metabolic remodeling characterized by normalization of metabolism, a higher NAD+/NADH ratio, and a sixfold upregulation of Sirt1. These changes were associated with altered extracellular vesicle miRNA content as well as proliferation and cytotoxicity parameters comparable to CMCWT cells. To test whether this metabolic improvement of CMCdb/db cells renders them suitable for cell therapy, we cultured CMCWT or CMCdb/db cells in 5.5  mM glucose and then injected them into infarcted hearts of non-diabetic mice (CMCWT,n = 17; CMCdb/db,n = 13; Veh,n = 14). Hemodynamic measurements performed 35 days after transplantation showed that, despite normalization of their properties in vitro, and unlike C...
Source: Basic Research in Cardiology - Category: Cardiology Source Type: research