Engineered 3D cardiac fibrotic tissue to study fibrotic remodeling
Open accessAbstract
Activation of cardiac fibroblasts into myofibroblasts is considered to play an essential role in cardiac remodeling and fibrosis. A limiting factor in studying this process is the spontaneous activation of cardiac fibroblasts when cultured on two‐dimensional (2D) culture plates. In this study, a simplified three‐dimensional (3D) hydrogel platform of contractile cardiac tissue, stimulated by transforming growth factor‐β1 (TGF‐β1), is presented to recapitulate a fibrogenic microenvironment. It is hypothesized that the quiescent state of cardiac fibroblasts can be maintained by mimicking the mechanical stiffness of native heart tissue. To test this hypothesis, a 3D cell culture model consisting of cardiomyocytes and cardiac fibroblasts encapsulated within a mechanically engineered gelatin methacryloyl hydrogel, is developed. The study shows that cardiac fibroblasts maintain their quiescent phenotype in mechanically tuned hydrogels. Additionally, treatment with a beta‐adrenergic agonist increases beating frequency, demonstrating physiologic‐like behavior of the heart constructs. Subsequently, quiescent cardiac fibroblasts within the constructs are activated by the exogenous addition of TGF‐β1. The expression of fibrotic protein markers (and the functional changes in mechanical stiffness) in the fibrotic‐like tissues are analyzed to validate the model. Overall, this 3D engineered culture model of contractile cardiac tissue enables controlled activation of cardiac fibroblasts, demonstrating the usability of this platform to study fibrotic remodeling.
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The diseased tissues showed asynchronous beating behavior and increased mechanical stiffness.
“The diseased tissues presented asynchronous beating behavior and increased mechanical stiffness.”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [310]
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- Authors
- Sadeghi, A. H., Shin, S. R., Deddens, J. C., Fratta, G., Mandla, S., Yazdi, I. K., Prakash, G., Antona, S., Demarchi, D., Buijsrogge, M. P., Sluijter, J. P. G., Hjortnaes, J., & Khademhosseini, A.
- Affiliations
- Brigham and Women's Hospital (US)
- University Medical Center Utrecht (NL)
- Politecnico di Torino (IT)
- Corresponding author
- Khademhosseini, Ali
- ORCID
- Venue
- Advanced Healthcare Materials
- Publisher
- Wiley
- Published
- 2017-05-12
- Volume
- 6
- Issue
- 11
- ISSN
- 2192-2640 (ISSN-L)
- 2192-2659
- PMC
- PMC5545804
- OpenAlex
- W2612053462
- Cited by
- 108
- References
- 77
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 19 · 2021: 21 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 1
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Advanced Healthcare Materials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- PORTO@Iris (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- PORTO Publications Open Repository TOrino (Politecnico di Torino) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institutes of Health (EB012597, AR057837, DE021468, HL099073, R56AI105024)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- myocardial fibrosis, cardiac remodeling, cardiac fibroblast activation, myofibroblast differentiation, gelatin methacryloyl hydrogel, stiffness, TGF-β1, cardiomyocytes, beta-adrenergic agonists, beating frequency, fibrotic microenvironment, engineered heart tissue
- MeSH terms
- Animals, Cells, Cultured, Fibroblasts, Fibrosis, Models, Cardiovascular, Cardiomyopathies, Myocardium, Rats, Sprague-Dawley, Hydrogels, Rats, Transforming Growth Factor beta1, Cellular Microenvironment
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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