The senolytic agent Dasatinib reduces fat accumulation in the heart and bone marrow of type 2 diabetic, obese mice and adipogenesis of human bone marrow pericytes

Abstract

Abstract Background Inflammaging, a chronic inflammatory state associated with aging and obesity, participates in the pathogenesis of cardiovascular disease and type 2 diabetes (T2D). Adipocyte accumulation in bone marrow (BM) may contribute to this phenomenon. Senolytic drugs, like Dasatinib, reportedly eliminate senescent preadipocytes. However, the effects of Dasatinib on fat deposits in the heart and BM remain unknown. Purposes This study aimed to identify the cellular source of adipocytes in human BM and determine whether treatment with Dasatinib reverses adiposity and improves cardiovascular function in T2D obese mice. Methods and results Human CD34neg CD45neg CD146pos pericytes (hBM-PCs) were sorted from BM mesenchymal stem cells (hBM-MSCs) by immunomagnetic beads. HBM-PCs showed a higher propensity to differentiate into Oil red O positive (pos) adipocytes after 21 days of stimulation in a pro-adipogenic medium (P=0.0299 vs. hBMSCs (hBM-MSCs except for hBM-PCs)). Dasatinib treatment reduced the number of viable cells (P=0.0034 vs. Vehicle (DMSO)) and the rate of adipocyte differentiation (P= 0.0179 vs. Vehicle). In a randomized blind study, Dasatinib (5 mg/kg) or vehicle (10% DMSO+90% PEG-300) was given by oral gavage to T2D, obese 21-week-old male BKS.Cg-+Leprdb/+Leprdb/OlaHsd (Db/Db) mice. Groups of animals were sacrificed at 1 or 4 weeks. Dasatinib reduced the Oil red O pos cells in the heart (P= 0.001 and 0.045) and BM (P= 0.018 and 0.0253) at both time points. Senescence marker p16INK4a expression and plasma adipokines levels were similar between the two groups at one week. With long-term treatment, the expression of senescence marker p16INK4a was significantly reduced in the murine hearts (P=0.035) and BM (P=0.068), whereas adipokines levels were similar. In vitro treatment of murine BM-MSCs with Dasatinib reduced the expression of p21Waf1/Cip1 (P= 0.030). VisualSonics 3D echocardiography showed similar diastolic and systolic function in Dasatinib- or Vehicle-treated mice: stroke volume (P= 0.494); ejection fraction (P= 0.701); fractional shorten (P= 0.807); and cardiac output (P= 0.437). Conclusion Pericytes are the primary source of adipocytes in human BM. The senolytic agent Dasatinib reduces pericyte commitment to adipogenesis. The senolytic agent prevented fat accumulation and cell senescence in the BM and heart of T2D mice. However, more prolonged treatment may be necessary for the reduced adiposity to translate into improvements in heart function.