Journal article
Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues
- Abstract:
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Introduction: Recent advances in human cardiac 3D approaches have yielded progressively more complex and physiologically relevant culture systems. However, their application in the study of complex pathological processes, such as inflammation and fibrosis, and their utility as models for drug development have been thus far limited.
Methods: In this work, we report the development of chamber-specific, vascularised human induced pluripotent stem cell-derived cardiac microtissues, which allow for the multi-parametric assessment of cardiac fibrosis.
Results: We demonstrate the generation of a robust vascular system in the microtissues composed of endothelial cells, fibroblasts and atrial or ventricular cardiomyocytes that exhibit gene expression signatures, architectural, and electrophysiological resemblance to in vivo-derived anatomical cardiac tissues. Following pro-fibrotic stimulation using TGFβ, cardiac microtissues recapitulated hallmarks of cardiac fibrosis, including myofibroblast activation and collagen deposition. A study of Ca2+ dynamics in fibrotic microtissues using optical mapping revealed prolonged Ca2+ decay, reflecting cardiomyocyte dysfunction, which is linked to the severity of fibrosis. This phenotype could be reversed by TGFβ receptor inhibition or by using the BET bromodomain inhibitor, JQ1.
Discussion: In conclusion, we present a novel methodology for the generation of chamber-specific cardiac microtissues that is highly scalable and allows for the multi-parametric assessment of cardiac remodelling and pharmacological screening.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 6.5MB, Terms of use)
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- Publisher copy:
- 10.3389/fcvm.2023.1156759
Authors
- Publisher:
- Frontiers Media
- Journal:
- Frontiers in Cardiovascular Medicine More from this journal
- Volume:
- 10
- Article number:
- 1156759
- Publication date:
- 2023-09-01
- Acceptance date:
- 2023-08-09
- DOI:
- EISSN:
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2297-055X
- Pmid:
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37727305
- Language:
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English
- Keywords:
- Pubs id:
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1533186
- Local pid:
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pubs:1533186
- Deposit date:
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2023-10-02
Terms of use
- Copyright holder:
- Reyat et al.
- Copyright date:
- 2023
- Rights statement:
- © 2023 Reyat, di Maio, Grygielska, Pike, Kemble, Rodriguez-Romero, Simoglou Karali, Croft, Psaila, Simões, Rayes and Khan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Notes:
- A CC BY or equivalent licence is applied to AAM arising from this submission, in accordance with the grant's open access conditions.
- Licence:
- CC Attribution (CC BY)
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