Project 10: Role of predisposing genetics, telomere signaling and crosstalk of cardiac fibroblasts and cardiomyocytes in a pluripotent stem cell model of sudden dilated cardiomyopathy
PI Göttingen: K. Streckfuß-Bömeke; PI London: A.M. Shah; PhD student: Wiebke Maurer
Scientific background
Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure with an estimated prevalence of 40 cases per 100 000 individuals, and characterized by left ventricular dilation and contractile dysfunction. Patient outcomes for DCM range from reduced quality of life due to heart failure and heart transplantation to sudden cardiac death between the ages of 20 and 60. By now, the molecular basis of majority of DCM cases remains unknown. However, mutations in more than 30 genes encoding cytoskeleton, sarcomere, splicing factors, nuclear envelope, and mitochondrial proteins have been discovered to cause the disease in up to 35% of the cases.
Besides genetic forms of DCM, also acquired age-dependent forms of DCM are major targets of pathophysiological analysis and therapeutic approaches. Thus, short telomeres are risk factors for age-associated diseases as DCM. Furthermore, there is evidence of cardiomyocyte-specific telomere shortening in genetic forms of DCM. It is proposed that mitochondrial dysfunction, often correlated with enhanced levels of ROS in cardiomyopathies, can drive telomere shortening and increase risk for cardiac disease. On the other hand, antioxidant enzymes can protect telomeres from acute oxidative damage. Therefore, telomere signaling represents new possibilities for therapeutic approaches. Nevertheless, it is still unclear, whether the diseased heart induces telomere shortening or whether shortened telomeres lead to heart failure.
There is increased recognition that myopathies may be the result of a complex interplay between both cardiomyocytes (CMs) and cardiac Fibroblasts (cFBs). The contribution of cFB to the pathophysiology of DCM is substantiated by the fact that fibrosis is one of the major phenotypic results in DCM. Human induced pluripotent stem cell-derived CMs (iPSC-CMs) in 2D-in vitro cultures are a favorable humanized model for personalized therapy. They were shown to recapitulate ventricular cardiomyopathies, channelopathies, mitochondrial disorders, as well as atrial disease mechanisms. However, 2D iPSC-CMs lack the presence and importance of other cell types in cardiac pathologies such as cFBs and the 3D environment.
Until now it is not known, (Maron et al, 2006) which genetic abberations or combinations of genetic variants as well as which pathomechanisms are the reason for severe forms of sudden DCM development, (Weintraub et al, 2017) which influence telomere-associated age- and mutation-based mechanisms have on the development of a DCM, and (Hershberger et al, 2011) which cardiac cell types including cFB and CMs are the main contributors in the development of DCM. The ability to generate human iPSCs provides a unique opportunity for modeling heart disease and for investigating the underlying mechanisms of DCM on a patient-specific level.
Research interests: Patient-specific induced pluripotent cells, cardiac disease modelling, cardiac regeneration
Speaker British Heart Foundation Centre of Research Excellence
Research interests: NADPH oxidases, redox signalling and heart failure
PhD student 3rd cohort
RP 10.3: Role of predisposing genetics, telomere signaling and crosstalk of cardiac fibroblasts and cardiomyocytes in a pluripotent stem cell model of sudden dilated cardiomyopathy