Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy
Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations...
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2025-07-01
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| Online Access: | https://doi.org/10.1186/s13287-025-04464-6 |
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| author | Jiabin Qin Qiangbing Yang Asier Ullate-Agote Vasco Sampaio-Pinto Laura Florit Inge Dokter Chrysoula Mathioudaki Lotte Middelberg Pilar Montero-Calle Paula Aguirre-Ruiz Joana de las Heras Rojo Zhiyong Lei Zeping Qiu Jin Wei Pim van der Harst Felipe Prosper Manuel M. Mazo Olalla Iglesias-García Monique C. Minnema Joost P. G. Sluijter Marish I.F.J. Oerlemans Alain van Mil |
| author_facet | Jiabin Qin Qiangbing Yang Asier Ullate-Agote Vasco Sampaio-Pinto Laura Florit Inge Dokter Chrysoula Mathioudaki Lotte Middelberg Pilar Montero-Calle Paula Aguirre-Ruiz Joana de las Heras Rojo Zhiyong Lei Zeping Qiu Jin Wei Pim van der Harst Felipe Prosper Manuel M. Mazo Olalla Iglesias-García Monique C. Minnema Joost P. G. Sluijter Marish I.F.J. Oerlemans Alain van Mil |
| author_sort | Jiabin Qin |
| collection | DOAJ |
| description | Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery. Methods and results Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils. Conclusions Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers. |
| format | Article |
| id | doaj-art-37370a90c6084fda8ed0e1cea808cb5d |
| institution | DOAJ |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-37370a90c6084fda8ed0e1cea808cb5d2025-08-20T03:04:34ZengBMCStem Cell Research & Therapy1757-65122025-07-0116111710.1186/s13287-025-04464-6Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathyJiabin Qin0Qiangbing Yang1Asier Ullate-Agote2Vasco Sampaio-Pinto3Laura Florit4Inge Dokter5Chrysoula Mathioudaki6Lotte Middelberg7Pilar Montero-Calle8Paula Aguirre-Ruiz9Joana de las Heras Rojo10Zhiyong Lei11Zeping Qiu12Jin Wei13Pim van der Harst14Felipe Prosper15Manuel M. Mazo16Olalla Iglesias-García17Monique C. Minnema18Joost P. G. Sluijter19Marish I.F.J. Oerlemans20Alain van Mil21Department of Cardiology, University Medical Center UtrechtCDL Research, University Medical Center UtrechtBiomedical Engineering Program, Technological Innovation Division, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA)Department of Cardiology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtBiomedical Engineering Program, Technological Innovation Division, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA)Hemato-Oncology Program, Cancer Division, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA)Hematology and Cell Therapy, Clínica Universidad de NavarraCDL Research, University Medical Center UtrechtDepartment of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, University Medical Center UtrechtHematology and Cell Therapy, Clínica Universidad de NavarraBiomedical Engineering Program, Technological Innovation Division, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA)Biomedical Engineering Program, Technological Innovation Division, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA)Department of Hematology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtDepartment of Cardiology, University Medical Center UtrechtAbstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery. Methods and results Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils. Conclusions Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers.https://doi.org/10.1186/s13287-025-04464-6Transthyretin amyloid cardiomyopathyIn vitro disease modelTTR fibrilsVariant TTRiPSC |
| spellingShingle | Jiabin Qin Qiangbing Yang Asier Ullate-Agote Vasco Sampaio-Pinto Laura Florit Inge Dokter Chrysoula Mathioudaki Lotte Middelberg Pilar Montero-Calle Paula Aguirre-Ruiz Joana de las Heras Rojo Zhiyong Lei Zeping Qiu Jin Wei Pim van der Harst Felipe Prosper Manuel M. Mazo Olalla Iglesias-García Monique C. Minnema Joost P. G. Sluijter Marish I.F.J. Oerlemans Alain van Mil Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy Stem Cell Research & Therapy Transthyretin amyloid cardiomyopathy In vitro disease model TTR fibrils Variant TTR iPSC |
| title | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy |
| title_full | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy |
| title_fullStr | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy |
| title_full_unstemmed | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy |
| title_short | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy |
| title_sort | uncovering cell type specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy |
| topic | Transthyretin amyloid cardiomyopathy In vitro disease model TTR fibrils Variant TTR iPSC |
| url | https://doi.org/10.1186/s13287-025-04464-6 |
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