title: Mechanotransduction is enhanced by the synergistic action of heterotypic cell interactions and TGF-β1.
abstract: With the use of planar substrates and collagen gels, the field of mechanotransduction has focused on the role of extracellular matrix stiffness, mechanical tension, and TGF-β1 in generating a more contractile fibroblast. However, little is known about the role of cell-cell interactions in inducing cellular contraction. We used 3-dimensional self-assembled microtissues, in which cell-cell interactions dominate, and a recently developed cell power assay (an assay for mechanotransduction) to quantify the effects of TGF-β1 vs. the heterotypic cell interface on the power exerted by pure normal human fibroblast (NHF) and pure rat hepatocyte 35 (H35) microtissues and their mixes. As a control, we found that TGF-β1 only doubled the power output of pure NHF and pure H35 microtissues, whereas the heterotypic environment resulted in a 5-fold increase in cell power (0.24±0.05 to 1.17±0.13 fJ/h). Seeding TGF-β1-treated NHFs with untreated H35 cells demonstrated that the heterotypic environment and TGF-β1 synergistically increase cell power by 22× by maximizing heterotypic cell interactions. Using a mathematical simulation of stress generation, we showed that tensile forces can be enhanced by heterotypic cell interactions. These data render a new understanding of how heterotypic cell interactions may increase cellular force generation during wound healing.
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Youssef
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Vivek B
authors.initials: VB
authors.lastname: Shenoy
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Morgan
mesh_terms: D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D053773:Transforming Growth Factor beta1