Sarcomere signaling in a patient-specific iPSC model of hypertrophic cardiomyopathy

by Hafiza Nosheen Saleem
Cumulative thesis
Date of Examination:2024-12-20
Date of issue:2025-03-07
Advisor:PD Dr. Antje Ebert
Referee:Prof. Dr. Peter Rehling
Referee:Prof. Dr. Ralph Kehlenbach
Persistent Address: http://dx.doi.org/10.53846/goediss-11119

 

 

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Abstract

English

Hypertrophic cardiomyopathy (HCM) is a severe cardiac disorder associated with ventricular hypertrophy, diastolic dysfunction, and arrhythmias, which can lead to heart failure. Inherited forms of HCM are frequently caused by mutations in sarcomere proteins, but many of the underlying molecular dysfunctions remain incompletely understood. To elucidate the sarcomere-dependent signaling in HCM, and its regulation by the actin filament network, we generated a patient-specific induced pluripotent stem cell (iPSC)-based model platform of HCM, employing an inherited HCM mutation (HCM1) in a z-disc localized, actin-organizing protein, as well as a well-characterized HCM mutation in a protein of the sarcomere thick filaments (HCM2). We tested the functions of specific actin-organizing proteins and their signaling activities in HCM1 patient-specific iPSC-derived cardiomyocytes (iPSC-CMs), compared to HCM2 iPSC-CMs, as well as WT controls. Alteration of some specific molecular and functional signalling defects was observed only in HCM1 iPSC-CMs, however, altered contractility and force generation defects were found in both HCM1 and HCM2 iPSC-CM models, compared to WT controls. Moreover, the HCM model platform contributed new understanding of the molecular basis of actin-organizing proteins in the organization of sarcomeres and their connections with the plasma membrane, which were found altered in HCM1 iPSC-CMs. Together, these sarcomere- and actin cytoskeleton-dependent dysfunctions in HCM1 iPSC-CMs may modulate disease-specific molecular signalling pathways that contribute to regulation of cardiomyocyte contractility in HCM. Thus, the findings of this study provided initial insights into subcellular disease phenotypes and molecular signaling dysfunctions in human patient-specific iPSC-CMs carrying different HCM mutations. In the future, these findings may assist the development of precision therapies for patients with HCM due to mutations in sarcomere proteins.
Keywords: Hypertrophic cardiomyopathy; iPSC-cardiomyocytes; disease modelling; sarcomere-organizing proteins; molecular signaling