Cellular modifications and interventions for the damaged heart

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Cellular modifications and interventions for the damaged heart

Type: Doctoral Thesis
Title: Cellular modifications and interventions for the damaged heart
Author: Engels, M.C.
Issue Date: 2016-05-11
Keywords: Regenerative medicine
Cardiomyocyte embryonic stem cells
Fibrosis arrhythmia
Optogenetics differentiation
Abstract: 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.
Promotor: Supervisor: M.J. Schalij Co-Supervisors: D.A. Pijnappels; A.A.F. de Vries
Faculty: LUMC
University: Leiden
Uri: urn:isbn:9789090296753
Handle: http://hdl.handle.net/1887/39392
 

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