Myofibroblasts mediate normal wound healing and upon chronic activation can contribute to the development of pathological conditions including organ fibrosis and cancer. Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT) during which epithelial cells exhibit drastic morphological changes and upregulate cytoskeletal associated proteins that enable exertion of large contractile forces and remodeling of the surrounding microenvironment. Increased matrix rigidity is a hallmark of fibrosis and tumor progression and mechanical tension has been identified as a regulator of EMT; however, the mechanisms governing the mechanical regulation of EMT are not completely understood. Here, we find that matrix rigidity regulates transforming growth factor (TGF)-β1-induced EMT, with rigid substrata enabling increased myofibroblast marker expression, cell morphology changes, and cytoskeletal reorganization while soft matrices block these changes. Furthermore, we find that matrix rigidity controls the subcellular localization of myocardin related transcription factor (MRTF)-A, a regulator of cytoskeletal protein expression that contributes to the acquisition of myogenic features during EMT. Results from these studies provide insight into how biophysical cues contribute to myofibroblast development from epithelial cells and may suggest ways to enhance wound healing or to engineer therapeutic solutions for fibrosis and cancer.

The reaction of [Cp*TaCl 4 ] with the potassium salt of carbazole (cbK, >3 equiv) in hydrocarbon solvents leads to the species [(C 5 Me 4 CH 2 )Ta(cb) 2 Cl] (1), in which one of the ring methyl C-H bonds of the Cp* ligand has been cleaved along with free cbH. Spectroscopic and structural studies of 1 show a lack of a plane of symmetry through the molecule with nonequivalent cb ligands. A minor component of the reaction mixture is believed to be the substitutional isomer 2, in which both carbazole ligands are equivalent. Alkylation of 1 with LiCH 2 SiMe 3 or PhCH 2 MgCl generates the corresponding monoalkyl derivatives [(C 5 Me 4 -CH 2 )Ta(cb) 2 (R)] (7 or 8, respectively). Structural studies of 1, 7, and 8 support an η 1 :η 5 -CH 2 C 5 Me 4 (σ:η 5 -CH 2 C 5 Me 4 ) description for the metalated ligands, with significant slippage toward an η 1 :η 3 -CH 2 C 5 Me 4 resonance form. To compare the extent of π-bonding between cb and dialkylamido ligands, the complex [(cb) 2 Ta(NMe 2 ) 3 ] (9) was synthesized and structurally characterized. The molecular structure of 9 consists of a tbp arrangement of nitrogen atoms with trans, axial cb ligands. The Ta-cb distances are 0.2 Å longer than the Ta-NMe 2 distances. An improved (safer) procedure for the synthesis of [Ta(NMe 2 ) 5 ] is presented.

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