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  Agonistic and antagonistic roles of fibroblasts and cardiomyocytes on viscoelastic stiffening of engineered human myocardium

Schlick, S. F., Spreckelsen, F., Tiburcy, M., Iyer, L. M., Meyer, T., Zelarayan, L. C., et al. (2019). Agonistic and antagonistic roles of fibroblasts and cardiomyocytes on viscoelastic stiffening of engineered human myocardium. Progress in Biophysics and Molecular Biology, 144, 51-60. doi:10.1016/j.pbiomolbio.2018.11.011.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-B214-E Version Permalink: http://hdl.handle.net/21.11116/0000-0003-C9B1-2
Genre: Journal Article

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 Creators:
Schlick, S. F., Author
Spreckelsen, Florian1, Author              
Tiburcy, M., Author
Iyer, L. M., Author
Meyer, T., Author
Zelarayan, L. C., Author
Luther, Stefan1, Author              
Parlitz, Ulrich1, Author              
Zimmermann, W. H., Author
Rehfeldt, F., Author
Affiliations:
1Research Group Biomedical Physics, Max Planck Institute for Dynamics and Self-Organization, Max Planck Society, ou_2063288              

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Free keywords: Engineered heart muscle; Fibroblasts; Cardiomyocytes; Collagen; Rheology; Nonlinear mechanics
 Abstract: Cardiomyocyte and stroma cell cross-talk is essential for the formation of collagen-based engineered heart muscle, including engineered human myocardium (EHM). Fibroblasts are a main component of the myocardial stroma. We hypothesize that fibroblasts, by compacting the surrounding collagen network, support the self-organization of cardiomyocytes into a functional syncytium. With a focus on early self-organization processes in EHM, we studied the molecular and biophysical adaptations mediated by defined populations of fibroblasts and embryonic stem cell-derived cardiomyocytes in a collagen type I hydrogel. After a short phase of cell-independent collagen gelation (30 min), tissue compaction was progressively mediated by fibroblasts. Fibroblast-mediated tissue stiffening was attenuated in the presence of cardiomyocytes allowing for the assembly of stably contracting, force-generating EHM within 4 weeks. Comparative RNA-sequencing data corroborated that fibroblasts are particularly sensitive to the tissue compaction process, resulting in the fast activation of transcription profiles, supporting heart muscle development and extracellular matrix synthesis. Large amplitude oscillatory shear (LAOS) measurements revealed nonlinear strain stiffening at physiological strain amplitudes (>2%), which was reduced in the presence of cells. The nonlinear stress-strain response could be characterized by a mathematical model. Collectively, our study defines the interplay between fibroblasts and cardiomyocytes during human heart muscle self-organization in vitro and underscores the relevance of fibroblasts in the biological engineering of a cardiomyogenesis-supporting viscoelastic stroma. We anticipate that the established mathematical model will facilitate future attempts to optimize EHM for in vitro (disease modelling) and in vivo applications (heart repair).

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Language(s): eng - English
 Dates: 2018-12-122019-07
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.pbiomolbio.2018.11.011
 Degree: -

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Title: Progress in Biophysics and Molecular Biology
Source Genre: Journal
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Pages: - Volume / Issue: 144 Sequence Number: - Start / End Page: 51 - 60 Identifier: -