Disease Modeling

Recreating diseases in a dish

Disease modeling using human induced pluripotent stem cells (hiPSCs) is a powerful and evolving approach in biomedical research. Patient- or donor-derived human iPSCs are differentiated into relevant cell types to study the cellular and molecular aspects of disease progression. Recent advancements in CRISPR-Cas genome-editing technologies have further expanded the applications of iPSCs to elucidate developmental pathways, disease modeling and therapeutic applications. CRISPR-Cas enables precise gene modifications, allowing researchers to correct disease-causing mutations for application in personalized medicine. The possibility to create tailored genetic models allows investigation of disease pathways with unparalleled accuracy. These diseases models are instrumental in understanding genetic disorders and developing targeted treatments. At IMTTS, in vitro cardiac disease modelling platforms are available in 2D monolayer or co-culture systems as well as 3D multicellular human cardiac organoids.

Living heart slices

We employ a combination of advanced physiological techniques, including force measurements, sarcomere shortening analysis (IonOptix, SarcTrack), and calcium imaging, to comprehensively investigate physiological alterations in disease models of hypertrophic and other forms of cardiomyopathies in close cooperation with MHHs department of cardiothoracic surgery. By utilizing multiple complementary approaches, we aim to gain deeper insights into the functional changes associated with this condition.

In addition to investigating the molecular and mechanical underpinnings of cardiomyopathies, we explore how environmental factors such as hypoxia, mechanical stimulation, and chemical cues influence heart muscle function, hypertrophy, and fibrosis development ex vivo in LMS. By systematically analyzing these effects, we seek to uncover new mechanisms that contribute to disease pathology and identify potential intervention points for therapeutic development.

Key references:

Chatterjee S, Leach-Mehrwald M, Huang CK, Xiao K, Fuchs M, Otto M, Lu D, Dang V, Winkler T, Dunbar CE, Thum T, Bär C. (2024) Telomerase is essential for cardiac differentiation and sustained metabolism of human cardiomyocytes. Cell Mol Life Sci81(1):196. https://doi.org/10.1007/s00018-024-05239-7

Jahn C, Juchem M, Sonnenschein K, Gietz A, Buchegger T, Lachmann N, Göhring G, Behrens YL, Bär C, Thum T, Hoepfner J. (2024) Generation of human induced pluripotent stem cell line MHHi029-A from a male Fabry disease patient carrying c.959A > T mutation. Stem Cell Res. 77:103404. https://doi.org/10.1016/j.scr.2024.103404

Juchem M, Lehmann N, Behrens YL, Bär C, Thum T, Hoepfner J. (2024) CRISPR/Cas9-based GLA knockout to generate the female Fabry disease human induced pluripotent stem cell line MHHi001-A-15. Stem Cell Res. 79:103478. https://doi.org/10.1016/j.scr.2024.103478

Foinquinos A, Batkai S, Genschel C, Viereck J, Rump S, Gyongyosi M, Traxler D, Riesenhuber M, Spannbauer A, Lukovic D, Weber N, Zlabinger K, Hasimbegovic E, Winkler J, Fiedler J, Dangwal S, Fischer M, de la Roche J, Wojciechowski D, Kraft T, Garamvolgyi R, Neitzel S, Chatterjee S, Yin X, Bar C, Mayr M, Xiao K, Thum T. (2020) Preclinical development of a miR-132 inhibitor for heart failure treatment. Nature Communications. 11(1):633. https://doi.org/10.1038/s41467-020-14349-2

Waleczek FJG, Cipriano G, Haas JA, Garg A, Pfanne A, Just A, Neumüller S, Hegermann J, Pich A, Radocaj A, Xiao K, Weber N, Thum T. (2024) Prolonged hypoxia in rat living myocardial slices affects function, expression and structure. Int J Mol Sci. 26(1):218. https://doi.org/10.3390/ijms26010218

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