Academic Journal
Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery
| العنوان: | Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery |
|---|---|
| المؤلفون: | Guanyi Huang, Anjali Bisaria, Devin L. Wakefield, Tracy M. Yamawaki, Xin Luo, Jingli A. Zhang, Patrick Vigneault, Jinghong Wang, Jeffrey D. Reagan, Oliver Oliverio, Hong Zhou, Chi-Ming Li, Olaia F. Vila, Songli Wang, Fady I. Malik, James J. Hartman, Christopher M. Hale |
| المصدر: | Stem Cell Reports, Vol 18, Iss 1, Pp 220-236 (2023) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2023 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | HIPSC-CM, sarcomere mutation, cardiomyopathy, disease modeling, 3D micro-tissues, contractility, Medicine (General), R5-920, Biology (General), QH301-705.5 |
| الوصف: | Summary: Titin-truncating variants (TTNtv) are the single largest genetic cause of dilated cardiomyopathy (DCM). In this study we modeled disease phenotypes of A-band TTNtv-induced DCM in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using genome editing and tissue engineering technologies. Transcriptomic, cellular, and micro-tissue studies revealed that A-band TTNtv hiPSC-CMs exhibit pathogenic proteinopathy, sarcomere defects, aberrant Na+ channel activities, and contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. However, TTNtv cellular defects did not interfere with the function of the core contractile machinery, the actin-myosin-troponin-Ca2+ complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomic changes that promote reversal of DCM disease signatures. Together, our findings elucidate the underlying pathogenic mechanisms of A-band TTNtv-induced DCM and demonstrate the validity of sarcomere modulators as potential therapeutics. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2213-6711 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2213671122005410; https://doaj.org/toc/2213-6711; https://doaj.org/article/30e3b255f0a347979433bbc120f0b28e |
| DOI: | 10.1016/j.stemcr.2022.11.008 |
| الاتاحة: | https://doi.org/10.1016/j.stemcr.2022.11.008 https://doaj.org/article/30e3b255f0a347979433bbc120f0b28e |
| رقم الانضمام: | edsbas.E48FE3E6 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 22136711 |
|---|---|
| DOI: | 10.1016/j.stemcr.2022.11.008 |