Browsing by Author "Carmo, Sara Martins do"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
- Exploring angiogenesis and cardiomyocyte differentiation in left ventricular noncompaction using patient derived hiPSCPublication . Carmo, Sara Martins do; Bragança, JoséLeft ventricular noncompaction (LVNC), is a rare cardiomyopathy characterized by a spongy myocardial structure, hyper-trabeculation and intra-trabecular recesses, resulting from failure of normal embryonic compaction of the myocardium. The prevalence of LVNC varies globally, between 9.5% in paediatric age and 0.05-0.25% in the general population. Multiple genetic mutations are associated with LVNC, affecting sarcomeric, cytoskeletal and mitochondrial functions. This study investigates the genetic mechanisms underlaying LVNC, focusing on mutations involved in heart diseases and their impact in cardiomyocyte differentiation and angiogenesis, with a special focus on ZSCAN10, SCN10A and VE-PTP, found mutated in the patient’s cells used in this study. Cardiomyocytes were differentiated from induced pluripotent stem cells (iPSCs) derived from a LVNC patient and a 1st degree healthy relative. Gene relative expression analysis of samples collected during cardiomyocyte differentiation, highlighted significant differences on in key genes, such as GATA4, ISL1, SOX17, KDR, VE-PTP, VEGFA, TNNT2 and NKX2.5 in patients derived cells compared to control cells. Among those, GATA4, ISL1 and NKX2.5, which were previously showed to cooperate for the differentiation and proliferation of cardiomyocytes, presented a significantly lower expression. SOX17, KDR and VEGFA have functions in cardiac vascularization, and the expression of SOX17 was higher in patient’s cells, while in the same conditions KDR and VEGFA were decreased at critical time points for endothelial cells differentiation. Thus, the expression of these genes, crucial for cardiomyocyte development and angiogenesis, were markedly altered in LVNC-derived cells compared to control cells. A Tube formation assay using endothelial cells from both LVNC-derived and control cells, to assess their ability to form capillary like structures. Remarkable differences were observed, with patient cells showing a delayed and an impaired tube formation, and a reduced vascular network complexity. Overall, our results argue that novel genetic and cellular mechanisms might be altered in the LVNC patient cells analysed.