Integrated phenotypic and transcriptomic characterization of desmin-related cardiomyopathy in hiPSC-derived cardiomyocytes and machine learning-based classification of disease features
Vivien Batoumeni , Yeranuhi Hovhannisyan , Bénédicte Gobert , Keyhan Alvandipour , Jennifer Arthur Ataam , Ombline Conrad , David Hoffmann , Nicolas Wiest-Daesslé , Jochen Dobner , José Américo Nabuco Leva Ferreira Freitas , Hakim Hocini , Zhenlin Li , Laurent Brino , Andrea Rossi , Onnik Agbulut , Peter Sommer , Pierre Joanne , Konstantinos Gkatzis
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引用次数: 0
Abstract
Desmin-related diseases are characterized by skeletal muscle weakness, cardiomyopathy, and respiratory dysfunction due to mutations in the desmin gene (DES), which encodes a protein essential for muscle cell integrity. This study investigates the effects of a pathogenic desmin mutation (DESE439K) in human cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) obtained from a patient carrying the DESE439K mutation, compared to cardiomyocytes derived from hiPSCs of three healthy donors. To further validate our findings a genome edited cell line has been obtained following the insertion of the mutation in a control hiPSC line. Using advanced technologies, including transcriptomics and phenotypic machine learning algorithms, we analyzed how this mutation disrupts cellular function and contributes to disease phenotypes. Our findings reveal that cardiomyocytes carrying DESE439K exhibit cytoplasmic protein aggregation, mitochondrial and sarcomere defects, and contractile dysfunctions, highlighting key phenotypic defects in desmin-related cardiomyopathy. Finaly, we developed a machine learning prediction model to classify cellular phenotypes, which can be used for translational research, including drug candidate screening. This research opens new avenues for understanding the molecular mechanisms of desmin-related cardiomyopathies and fosters the development of novel therapeutic strategies.
期刊介绍:
The European Journal of Cell Biology, a journal of experimental cell investigation, publishes reviews, original articles and short communications on the structure, function and macromolecular organization of cells and cell components. Contributions focusing on cellular dynamics, motility and differentiation, particularly if related to cellular biochemistry, molecular biology, immunology, neurobiology, and developmental biology are encouraged. Manuscripts describing significant technical advances are also welcome. In addition, papers dealing with biomedical issues of general interest to cell biologists will be published. Contributions addressing cell biological problems in prokaryotes and plants are also welcome.