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

Author information

Affiliations

  • 1. Institute of Pharmacology and Toxicology, University Medical Center Göttingen, 37075, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075, Göttingen, Germany.
      Authors
    • Schlick SF 1
    • Tiburcy M 1
    • Iyer LM 1
    • Meyer T 1
    • Zelarayan LC 1
    • Zimmermann WH 1
    (6 authors)
  • 2. DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075, Göttingen, Germany; University of Göttingen, Institute for Nonlinear Dynamics, 37077, Göttingen, Germany; Max Planck Institute for Dynamics and Self-Organization, 37077, Göttingen, Germany.
      Authors
    • Spreckelsen F 2
    • Parlitz U 2
    (2 authors)
  • 3. Institute of Pharmacology and Toxicology, University Medical Center Göttingen, 37075, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075, Göttingen, Germany; University of Göttingen, Institute for Nonlinear Dynamics, 37077, Göttingen, Germany; Max Planck Institute for Dynamics and Self-Organization, 37077, Göttingen, Germany.
      Authors
    • Luther S 3
    (1 author)
  • 4. University of Göttingen, 3rd Institute of Physics - Biophysics, 37077, Göttingen, Germany.
      Authors
    • Rehfeldt F 4
    (1 author)

ORCIDs linked to this article

Progress in Biophysics and Molecular Biology, 12 Dec 2018, 144:51-60
https://doi.org/10.1016/j.pbiomolbio.2018.11.011 PMID: 30553553 

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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Read article at publisher's site: https://doi.org/10.1016/j.pbiomolbio.2018.11.011

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Funding 

Funders who supported this work.

Collaborative Research Center SFB (1)

DZHK

    IRTG (1)

    SFB (1)

    Transcriptome and Genome Analysis Laboratory (TAL)

      University Medical Center Göttingen