Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes

REBUZZINI P; CEBRAL, E; FASSINA L; REDI C; ZUCCOTTI M; GARAGNA S

Scientific Reports

Nature

Año: 2015

2045-2322

Arsenic, a widelydiffused environmental toxicant, exerts toxic effects on the cardiovascular system andspecifically on cardiomyocytes. However, the knowledge of its effects duringthe process of cardiomyocytes differentiation is meagre. Here, we differentiated mouse embryonic stem cells into cardiomyocytes inthe presence of 0.1 or 1.0 µM As2O3. At 1.0 µM As2O3concentration, when compared to controls, treated samples show: 1) reducedsize in diameter of embryoid bodies; 2) decreased expression of Brachyury (mesoderm), Nkx2.5 (cardiac mesoderm), Tnnc1 (cardiomyocytes) and increased Gata-4 (cardiac mesoderm); 3)inefficient and delayed acquisition of the beating capacity, 4) smaller beating areas; 5) reductionof thebeat frequency, contractility, contraction force and kinetic energy (kinematics and dynamics properties); 6) cardiomyocytes with disorganized and disoriented sarcomeres(immunofluorescence with á-actinin and TroponinT antibodies) and 7) altered syncytial organisation, as evidenced by morerarefied Connexin 43 foci distribution. At the lower 0.1 µM concentration,although neither the timing of acquisition of thebeating capacity nor the pattern of expression of cardiac-specific genes are affectedand the cardiac junctions and the sarcomeres in the syncytia are lessfrequently disorganised, the kinematics and dynamics properties of the beatingsyncytia are significantly altered. Overall, theseresults indicate that the presence of As2O3 throughoutdifferentiation leads to the formation of morphologically and functionallyaltered cardiomyocytes. The magnitude of the damage depends on theconcentration: whilst at the highest dose the differentiation process isaltered since its early stages, at the lowest dose the effects are evident onlyon differentiated cardiomyocytes.