Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy

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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Main Authors: 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
Format: Article
Language:English
Published: BMC 2025-07-01
Series:Stem Cell Research & Therapy
Subjects:
Transthyretin amyloid cardiomyopathy
In vitro disease model
TTR fibrils
Variant TTR
iPSC
Online Access:https://doi.org/10.1186/s13287-025-04464-6
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Summary: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.
ISSN:1757-6512

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