Scientific publications
Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy
Jiabin Qin 1 2, Qiangbing Yang 3, Asier Ullate-Agote 4, Vasco Sampaio-Pinto 1 2, Laura Florit 1 2 5, Inge Dokter 1 2, Chrysoula Mathioudaki 1 2, Lotte Middelberg 1 2, Pilar Montero-Calle 4 6 7, Paula Aguirre-Ruiz 7, Joana de Las Heras Rojo 6 7, Zhiyong Lei 3, Zeping Qiu 8 9, Jin Wei 8 9, Pim van der Harst 1, Felipe Prosper 6 7 10, Manuel M Mazo 4 6, Olalla Iglesias-García 4, Monique C Minnema 11, Joost P G Sluijter 1 2, Marish I F J Oerlemans # 12 13 14 15, Alain van Mil # 16 17
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.
CITA DEL ARTÍCULO Stem Cell Res Ther. 2025 Jul 6;16(1):352. doi: 10.1186/s13287-025-04464-6.
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