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A key trafficking route distributes cargo taken up by clathrin-mediated endocytosis (CME) via early endosomes. The highly dynamic nature of the endosome network presents a challenge for its quantitative analysis, and theoretical modelling approaches can assist in elucidating the organization of the endosome trafficking system. Here, we introduce a new computational modelling approach for assessment of endosome distributions. We employed a model of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with inherited mutations causing dilated cardiomyopathy (DCM). In this model, vesicle distribution is defective due to impaired CME-dependent signaling, resulting in plasma membrane-localized early endosomes. We recapitulated this in iPSC-CMs carrying two different mutations, TPM1-L185F and TnT-R141W (MUT), using 3D confocal imaging as well as super-resolution STED microscopy. We computed scaled distance distributions of EEA1-positive vesicles based on a spherical approximation of the cell. Employing this approach, 3D spherical modelling identified a bi-modal segregation of early endosome populations in MUT iPSC-CMs, compared to WT controls. Moreover, spherical modelling confirmed reversion of the bi-modal vesicle localization in RhoA II-treated MUT iPSC-CMs. This reflects restored, homogeneous distribution of early endosomes within MUT iPSC-CMs following rescue of CME-dependent signaling via RhoA II-dependent RhoA activation. Overall, our approach enables assessment of early endosome distribution in cell-based disease models. This new method may provide further insight into the dynamics of endosome networks in different physiological scenarios.<\/jats:p>","DOI":"10.3390\/cells13110923","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:27:59Z","timestamp":1716805679000},"page":"923","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["3D Computational Modeling of Defective Early Endosome Distribution in Human iPSC-Based Cardiomyopathy Models"],"prefix":"10.3390","volume":"13","author":[{"given":"Hafiza Nosheen","family":"Saleem","sequence":"first","affiliation":[{"name":"Heart Research Center Goettingen, Department of Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, 37077 Goettingen, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezda","family":"Ignatyeva","sequence":"additional","affiliation":[{"name":"Heart Research Center Goettingen, Department of Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, 37077 Goettingen, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3277-0544","authenticated-orcid":false,"given":"Christiaan","family":"Stuut","sequence":"additional","affiliation":[{"name":"Research Group Mitochondrial Structure and Dynamics, Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, 37077 Goettingen, Germany"},{"name":"Clinic of Neurology, High Resolution Microscopy, University Medical Center Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8028-3121","authenticated-orcid":false,"given":"Stefan","family":"Jakobs","sequence":"additional","affiliation":[{"name":"Research Group Mitochondrial Structure and Dynamics, Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, 37077 Goettingen, Germany"},{"name":"Clinic of Neurology, High Resolution Microscopy, University Medical Center Goettingen, 37075 Goettingen, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Habeck","sequence":"additional","affiliation":[{"name":"Microscopic Image Analysis, 39065 Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3642-242X","authenticated-orcid":false,"given":"Antje","family":"Ebert","sequence":"additional","affiliation":[{"name":"Heart Research Center Goettingen, Department of Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, 37077 Goettingen, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,27]]},"reference":[{"key":"ref_1","first-page":"2346","article-title":"[Induction of pluripotent stem cells from mouse fibroblast cultures]","volume":"51","author":"Yamanaka","year":"2006","journal-title":"Tanpakushitsu Kakusan Koso"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nmeth.1593","article-title":"Chemically defined conditions for human iPSC derivation and culture","volume":"8","author":"Chen","year":"2011","journal-title":"Nat. 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Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nature09747","article-title":"Modelling the long QT syndrome with induced pluripotent stem cells","volume":"471","author":"Itzhaki","year":"2011","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jacc.2014.04.057","article-title":"Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing","volume":"64","author":"Wang","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.stem.2012.10.010","article-title":"Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells","volume":"12","author":"Lan","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"130ra147","DOI":"10.1126\/scitranslmed.3003552","article-title":"Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy","volume":"4","author":"Sun","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41598-019-56597-3","article-title":"Troponin destabilization impairs sarcomere-cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients","volume":"10","author":"Dai","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1161\/CIRCRESAHA.122.321157","article-title":"An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes","volume":"133","author":"Dai","year":"2023","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/35052055","article-title":"Rab proteins as membrane organizers","volume":"2","author":"Zerial","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wandinger-Ness, A., and Zerial, M. (2014). Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb. Perspect. Biol., 6.","DOI":"10.1101\/cshperspect.a022616"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e32282","DOI":"10.7554\/eLife.32282","article-title":"Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria","volume":"7","author":"Hsu","year":"2018","journal-title":"Elife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1002\/1873-3468.14189","article-title":"Non-negative blind deconvolution for signal processing in a CRISPR-edited iPSC-cardiomyocyte model of dilated cardiomyopathy","volume":"595","author":"Xu","year":"2021","journal-title":"FEBS Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"255ra130","DOI":"10.1126\/scitranslmed.3009027","article-title":"Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system","volume":"6","author":"Ebert","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E1848","DOI":"10.1073\/pnas.1200250109","article-title":"Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling","volume":"109","author":"Lian","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nprot.2012.150","article-title":"Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt\/beta-catenin signaling under fully defined conditions","volume":"8","author":"Lian","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1161\/CIRCRESAHA.118.313973","article-title":"Proteasome-Dependent Regulation of Distinct Metabolic States During Long-Term Culture of Human iPSC-Derived Cardiomyocytes","volume":"125","author":"Ebert","year":"2019","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.stem.2016.07.006","article-title":"Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro","volume":"19","author":"Matsa","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Del Conte-Zerial, P., Brusch, L., Rink, J.C., Collinet, C., Kalaidzidis, Y., Zerial, M., and Deutsch, A. (2008). Membrane identity and GTPase cascades regulated by toggle and cut-out switches. Mol. Syst. Biol., 4.","DOI":"10.1038\/msb.2008.45"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1016\/j.cub.2012.06.021","article-title":"A general theoretical framework to infer endosomal network dynamics from quantitative image analysis","volume":"22","author":"Foret","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1093\/cvr\/cvv017","article-title":"Modelling sarcomeric cardiomyopathies in the dish: From human heart samples to iPSC cardiomyocytes","volume":"105","author":"Eschenhagen","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8206","DOI":"10.1073\/pnas.97.15.8206","article-title":"Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission","volume":"97","author":"Klar","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nrm.2017.71","article-title":"Fluorescence nanoscopy in cell biology","volume":"18","author":"Sahl","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e104105","DOI":"10.15252\/embj.2019104105","article-title":"MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation","volume":"39","author":"Stephan","year":"2020","journal-title":"EMBO J."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/11\/923\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:48:57Z","timestamp":1760107737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/11\/923"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,27]]},"references-count":26,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["cells13110923"],"URL":"https:\/\/doi.org\/10.3390\/cells13110923","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,27]]}}}