Mechanical Cell Reprogramming on Tissue-Mimicking Hydrogels for Cancer Cell Transdifferentiation

Disrupted matrix mechanics have been found to be highly associated with increased risks of many diseases, including neurodegenerative diseases and cancers. For centuries, the aged tissue matrix has been found to lose its mechanical integrity and exhibit altered biophysical properties. Whether the mechanical properties of matrix serve as a regulator for maintaining the health and function of cells remains unknown. Here, we propose that cells cultured within a tissue-mimicking mechanical microenvironment exhibit reprogrammed cellular behaviors. We first construct a tissue-mimicking hydrogel by combining both viscoelastic and nonlinear elastic components, on which fibroblasts crowd together to form mesenchymal aggregates instead of individually spreading out. The mesenchymal aggregates not only obtain the elevated expression of stemness genes but also exhibit enhanced bidirectional differentiation potentials. The formation of mesenchymal aggregates happens through the reorganization of the collagen network induced by the enhanced cell contraction. Compromising the cell contraction not only prevents the formation of mesenchymal aggregates but also eliminates cell reprogramming. Additionally, this mechanical reprogramming with tissue-mimicking hydrogels has been applied to non-small-lung cancer cells and promotes their adipogenic transdifferentiation, which eventually reverses their epithelial-to-mesenchymal transition genes and suppresses the expression of oncogenes/pro-oncogenes. Thus, our study paves the way for both regenerative medicine and cancer treatments with an approach termed mechanical reprogramming on tissue-mimicking hydrogels.