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Abstract Mesenchymal–epithelial transition (MET) is essential for tissue and organ development and is thought to contribute to cancer by enabling the establishment of metastatic lesions. Despite its importance in both health and disease, there is a lack of in vitro platforms to study MET and little is known about the regulation of MET by mechanical cues. Here, hyaluronic acid‐based hydrogels with dynamic and tunable stiffnesses mimicking that of normal and tumorigenic mammary tissue are synthesized. The platform is then utilized to examine the response of mammary epithelial cells and breast cancer cells to dynamic modulation of matrix stiffness. Gradual softening of the hydrogels reduces proliferation and increases apoptosis of breast cancer cells. Moreover, breast cancer cells exhibit temporal changes in cell morphology, cytoskeletal organization, and gene expression that are consistent with mesenchymal–epithelial plasticity as the stiffness of the matrix is reduced. A reduction in matrix stiffness attenuates the expression of integrin‐linked kinase, and inhibition of integrin‐linked kinase impacts proliferation, apoptosis, and gene expression in cells cultured on stiff and dynamic hydrogels. Overall, these findings reveal intermediate epithelial/mesenchymal states as cells move along a matrix stiffness‐mediated MET trajectory and suggest an important role for matrix mechanics in regulating mesenchymal–epithelial plasticity. 

Abstract Thermogels that exhibit a sol‐gel transition at body temperature represent a promising class of injectable biomaterials for biomedical applications. Thermogels reported thus far are generally composed of amphiphilic block copolymer micelles with an isotropic thermosensitive surface that induces intermicellar aggregation upon heating. Despite the promise, these hydrogels exhibit low mechanical strengths due to their uncontrollable aggregation resulting in void formation. To gain better control over intermicellar assembly, herein a novel thermogel design concept is presented based on patchy polymeric micelles bearing multiple thermosensitive surface domains. These domains serve as “patches” to bridge the micelles to form a percolated network structure. Patchy micelles are prepared from a binary mixture of amphiphilic block copolymers: Poly(N‐acryloylmorpholine)‐b‐poly(N‐benzylacrylamide) (PAM‐PBzAM) and poly (N‐isopropyl acrylamide)‐b‐poly(N‐benzylacrylamide) (PNIPAM‐PBzAM), where PBzAM, PAM and PNIPAM are the hydrophobic, hydrophilic and thermosensitive blocks, respectively. At 25 °C, the polymers self‐assembled into mixed shell micelles having a phase‐separated shell with PAM‐ and PNIPAM‐rich domains. At 37 °C, the PNIPAM domains undergo a hydrophilic‐to‐hydrophobic transition to induce intermicellar assembly into entangled worm‐like structures resulting in hydrogel formation. Patchy micelles form a homogeneous network structure without voids. The micelle design significantly affects the inter‐micellar assembly, the thermogelling behavior, and the mechanical properties of the hydrogels.