Mechanotransduction is enhanced by the synergistic action of heterotypic cell interactions and TGF-β1

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-beta 1 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-beta 1 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-beta 1 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-beta 1-treated NHFs with untreated H35 cells demonstrated that the heterotypic environment and TGF-beta 1 synergistically increase cell power by 22x 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.-Youssef, J., Chen, P., Shenoy, V. B., Morgan, J. R. Mechanotransduction is enhanced by the synergistic action of heterotypic cell interactions and TGF-beta 1. FASEB J. 26, 2522-2530 (2012). www.fasebj.org