Advanced in vitro modeling to study the paradox of mechanically induced cardiac fibrosis

Tom Bracco Gartner, Jeroen Stein, Dimitri Muylaert, Carlijn Bouten, Pieter Doevendans, Ali Khademhosseini, Willem Suyker, Joost Sluijter, Jesper Hjortnaes (Corresponding author)

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In heart failure, cardiac fibrosis is the result of an adverse remodeling process. Collagen is continuously synthesized in the myocardium in an ongoing attempt of the heart to repair itself. The resulting collagen depositions act counterproductively, causing diastolic dysfunction and disturbing electrical conduction. Efforts to treat cardiac fibrosis specifically have not been successful and the molecular etiology is only partially understood. The differentiation of quiescent cardiac fibroblasts to extracellular matrix-depositing myofibroblasts is a hallmark of cardiac fibrosis and a key aspect of the adverse remodeling process. This conversion is induced by a complex interplay of biochemical signals and mechanical stimuli. Tissue engineered 3D-models to study cardiac fibroblast behavior in vitro indicate that cyclic strain can activate a myofibroblast-phenotype. This raises the question how fibroblast quiescence is maintained in the healthy myocardium, despite continuous stimulation of ultimately pro-fibrotic mechanotransductive pathways. In this review, we will discuss the convergence of biochemical and mechanical differentiation signals of myofibroblasts, and hypothesize how these affect this paradoxical quiescence.

Original languageEnglish
Pages (from-to)100-114
Number of pages15
JournalTissue Engineering. Part C: Methods
Issue number2
Early online date6 Jan 2021
Publication statusPublished - 1 Feb 2021


  • cardiac fibroblast
  • disease modeling
  • mechanotransduction
  • myocardial fibrosis
  • organs-on-chips
  • Mechanotransduction, Cellular
  • Myocardium/pathology
  • Humans
  • Fibrosis
  • Myofibroblasts
  • Fibroblasts/pathology


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