Cellular modifications and interventions for the damaged heart

Engels, M.C. (2016)

Doctoral Thesis

 

The aim of this thesis was to explore cellular modification processes associated with heart disease, as well as harnessing its potential for treatment and prevention of detrimental electrophysiological consequences of heart disease. For regenerative cell replacement therapies, optimal differentiation strategies can give rise to efficient generation of mature cardiomyocytes. Insuline-like growth factor (IGF) was found to selectively expand early mesodermal cardiac precursor cell populations in an embryonic stem cell model. Timed exposure of differentiating stem cells to IGF can significantly increase the efficiency of cardiac differentiation. In addition to cell replacement therapy, scar substrate can be modified in order to alter its electrophysiological properties. Fusion of fibroblastic scar cells with surrounding cardiomyocytes reduced pro-arrhtyhmic features through several mechanisms, including more negative mean diastolic potential, enhanced outward Kv current and increased connexin43 expression. Remodelled ventricular tissue is characterized by fibrosis and connexin43 downregulation. This creates an arrhythmogenic substrate, as it gives rise to action potential duration (APD) alternans. Organization of discrete areas of APD alternans is associated with stable reentry formation. By optogenetic modification of cardiomyocytes, re-entry could be effectively terminated by brief light stimuli. Cellular modification is a promising treatment strategy for heart disease.

 

• Regenerative medicine
• Cardiomyocyte embryonic stem cells
• Fibrosis arrhythmia
• Optogenetics differentiation

• All authors: Engels, M.C.
• Supervisor: Schalij, M.J.
• Co-supervisor: Pijnappels, D.A.; Vries, A.A.F. de
• Committee: Atsma, D.E.; Christoffels, V.M.; Wu, S.M.; Zeppenfeld, K.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center Graduate School, LUMC, Leiden University
• Date: 2016-05-11
• ISBN (print): 9789090296753