Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues
IntroductionRecent 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 developm...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1156759/full |
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| author | Jasmeet S. Reyat Jasmeet S. Reyat Alessandro di Maio Beata Grygielska Jeremy Pike Jeremy Pike Samuel Kemble Antonio Rodriguez-Romero Christina Simoglou Karali Adam P. Croft Bethan Psaila Bethan Psaila Filipa Simões Julie Rayes Julie Rayes Abdullah O. Khan Abdullah O. Khan |
| author_facet | Jasmeet S. Reyat Jasmeet S. Reyat Alessandro di Maio Beata Grygielska Jeremy Pike Jeremy Pike Samuel Kemble Antonio Rodriguez-Romero Christina Simoglou Karali Adam P. Croft Bethan Psaila Bethan Psaila Filipa Simões Julie Rayes Julie Rayes Abdullah O. Khan Abdullah O. Khan |
| author_sort | Jasmeet S. Reyat |
| collection | DOAJ |
| description | IntroductionRecent 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.MethodsIn 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.ResultsWe 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.DiscussionIn 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. |
| first_indexed | 2024-03-12T11:27:01Z |
| format | Article |
| id | doaj.art-3399289f4d04440a98842fe8c911f425 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-12T11:27:01Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-3399289f4d04440a98842fe8c911f4252023-09-01T07:08:28ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-09-011010.3389/fcvm.2023.11567591156759Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissuesJasmeet S. Reyat0Jasmeet S. Reyat1Alessandro di Maio2Beata Grygielska3Jeremy Pike4Jeremy Pike5Samuel Kemble6Antonio Rodriguez-Romero7Christina Simoglou Karali8Adam P. Croft9Bethan Psaila10Bethan Psaila11Filipa Simões12Julie Rayes13Julie Rayes14Abdullah O. Khan15Abdullah O. Khan16College of Medical and Dental Sciences, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United KingdomDepartment of Physiology, Anatomy and Genetics, Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, United KingdomThe Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Birmingham, United KingdomCollege of Medical and Dental Sciences, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United KingdomCollege of Medical and Dental Sciences, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United KingdomThe Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Birmingham, United KingdomRheumatology Research Group, College of Medical and Dental Sciences, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United KingdomRadcliffe Department of Medicine and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomRadcliffe Department of Medicine and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomRheumatology Research Group, College of Medical and Dental Sciences, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United KingdomRadcliffe Department of Medicine and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomCancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomDepartment of Physiology, Anatomy and Genetics, Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, United KingdomCollege of Medical and Dental Sciences, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United KingdomThe Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Birmingham, United KingdomCollege of Medical and Dental Sciences, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United KingdomRadcliffe Department of Medicine and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomIntroductionRecent 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.MethodsIn 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.ResultsWe 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.DiscussionIn 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.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1156759/full3D cardiac microtissuesinduced pluripotent stem cellstissue engineeringcardiac fibrosiscardiomyocytes |
| spellingShingle | Jasmeet S. Reyat Jasmeet S. Reyat Alessandro di Maio Beata Grygielska Jeremy Pike Jeremy Pike Samuel Kemble Antonio Rodriguez-Romero Christina Simoglou Karali Adam P. Croft Bethan Psaila Bethan Psaila Filipa Simões Julie Rayes Julie Rayes Abdullah O. Khan Abdullah O. Khan Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues Frontiers in Cardiovascular Medicine 3D cardiac microtissues induced pluripotent stem cells tissue engineering cardiac fibrosis cardiomyocytes |
| title | Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues |
| title_full | Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues |
| title_fullStr | Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues |
| title_full_unstemmed | Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues |
| title_short | Modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues |
| title_sort | modelling the pathology and treatment of cardiac fibrosis in vascularised atrial and ventricular cardiac microtissues |
| topic | 3D cardiac microtissues induced pluripotent stem cells tissue engineering cardiac fibrosis cardiomyocytes |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1156759/full |
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