title: On-chip assessment of human primary cardiac fibroblasts proliferative responses to uniaxial cyclic mechanical strain.
abstract: Cardiac cell function is substantially influenced by the nature and intensity of the mechanical loads the cells experience. Cardiac fibroblasts (CFs) are primarily involved in myocardial tissue remodeling: at the onset of specific pathological conditions, CFs activate, proliferate, differentiate, and critically alter the amount of myocardial extra-cellular matrix with important consequences for myocardial functioning. While cyclic mechanical strain has been shown to increase matrix synthesis of CFs in vitro, the role of mechanical cues in CFs proliferation is unclear. We here developed a multi-chamber cell straining microdevice for cell cultures under uniform, uniaxial cyclic strain. After careful characterization of the strain field, we extracted human heart-derived CFs and performed cyclic strain experiments. We subjected cells to 2% or 8% cyclic strain for 24 h or 72 h, using immunofluorescence to investigate markers of cell morphology, cell proliferation (Ki67, EdU, phospho-Histone-H3) and subcellular localization of the mechanotransduction-associated transcription factor YAP. Cell morphology was affected by cyclic strain in terms of cell area, cell and nuclear shape and cellular alignment. We additionally observed a strain intensity-dependent control of cell growth: a significant proliferation increase occurred at 2% cyclic strain, while time-dependent effects took place upon 8% cyclic strain. The YAP-dependent mechano-transduction pathway was similarly activated in both strain conditions. These results demonstrate a differential effect of cyclic strain intensity on human CFs proliferation control and provide insights into the YAP-dependent mechano-sensing machinery of human CFs.
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy. giovannistefano.ugolini@polimi.it.
authors.forename: Giovanni Stefano
authors.initials: GS
authors.lastname: Ugolini
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rasponi
authors.affiliation: BioSyM IRG, Singapore-MIT Alliance for Research and Technology, Singapore.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pavesi
authors.affiliation: Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Santoro
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Roger
authors.initials: R
authors.lastname: Kamm
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Gianfranco Beniamino
authors.initials: GB
authors.lastname: Fiore
authors.affiliation: Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pesce
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Soncini
mesh_terms: D015415:Biomarkers / Q000032:analysis; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003584:Cytological Techniques / Q000295:instrumentation / Q000379:methods; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular; D013314:Stress, Mechanical
chemical_list: D015415:Biomarkers
keywords: cell proliferation; cyclic strain; human cardiac fibroblasts; mechanobiology; mechanotransduction; microdevice