date: 2024-06-06T11:36:16Z
pdf:unmappedUnicodeCharsPerPage: 0
pdf:PDFVersion: 1.7
pdf:docinfo:title: 3D Computational Modeling of Defective Early Endosome Distribution in Human iPSC-Based Cardiomyopathy Models
xmp:CreatorTool: LaTeX with hyperref
Keywords: endosomes; human iPSCs; computational modelling; signal processing; signal transduction; STED; dilated cardiomyopathy; heart failure
access_permission:modify_annotations: true
access_permission:can_print_degraded: true
subject: Intracellular cargo delivery via distinct transport routes relies on vesicle carriers. 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.
dc:creator: Hafiza Nosheen Saleem, Nadezda Ignatyeva, Christiaan Stuut, Stefan Jakobs, Michael Habeck and Antje Ebert
dcterms:created: 2024-06-06T11:24:04Z
Last-Modified: 2024-06-06T11:36:16Z
dcterms:modified: 2024-06-06T11:36:16Z
dc:format: application/pdf; version=1.7
title: 3D Computational Modeling of Defective Early Endosome Distribution in Human iPSC-Based Cardiomyopathy Models
Last-Save-Date: 2024-06-06T11:36:16Z
pdf:docinfo:creator_tool: LaTeX with hyperref
access_permission:fill_in_form: true
pdf:docinfo:keywords: endosomes; human iPSCs; computational modelling; signal processing; signal transduction; STED; dilated cardiomyopathy; heart failure
pdf:docinfo:modified: 2024-06-06T11:36:16Z
meta:save-date: 2024-06-06T11:36:16Z
pdf:encrypted: false
dc:title: 3D Computational Modeling of Defective Early Endosome Distribution in Human iPSC-Based Cardiomyopathy Models
modified: 2024-06-06T11:36:16Z
cp:subject: Intracellular cargo delivery via distinct transport routes relies on vesicle carriers. 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.
pdf:docinfo:subject: Intracellular cargo delivery via distinct transport routes relies on vesicle carriers. 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.
Content-Type: application/pdf
pdf:docinfo:creator: Hafiza Nosheen Saleem, Nadezda Ignatyeva, Christiaan Stuut, Stefan Jakobs, Michael Habeck and Antje Ebert
X-Parsed-By: org.apache.tika.parser.DefaultParser
creator: Hafiza Nosheen Saleem, Nadezda Ignatyeva, Christiaan Stuut, Stefan Jakobs, Michael Habeck and Antje Ebert
meta:author: Hafiza Nosheen Saleem, Nadezda Ignatyeva, Christiaan Stuut, Stefan Jakobs, Michael Habeck and Antje Ebert
dc:subject: endosomes; human iPSCs; computational modelling; signal processing; signal transduction; STED; dilated cardiomyopathy; heart failure
meta:creation-date: 2024-06-06T11:24:04Z
created: 2024-06-06T11:24:04Z
access_permission:extract_for_accessibility: true
access_permission:assemble_document: true
xmpTPg:NPages: 16
Creation-Date: 2024-06-06T11:24:04Z
pdf:charsPerPage: 3892
access_permission:extract_content: true
access_permission:can_print: true
meta:keyword: endosomes; human iPSCs; computational modelling; signal processing; signal transduction; STED; dilated cardiomyopathy; heart failure
Author: Hafiza Nosheen Saleem, Nadezda Ignatyeva, Christiaan Stuut, Stefan Jakobs, Michael Habeck and Antje Ebert
producer: pdfTeX-1.40.25
access_permission:can_modify: true
pdf:docinfo:producer: pdfTeX-1.40.25
pdf:docinfo:created: 2024-06-06T11:24:04Z