Hydrogel with cell-cell adhesion cues enhances neural regeneration

Cell-cell adhesion is crucial for maintaining cell functions and the integrity of tissue structure in organisms. However, cell-cell adhesion cue has not been effectively replicated in biomaterials and cell-cell adhesion associated mechanisms that enhance neural regeneration remained largely unexplored. Here, we present a diffusive N-cadherin functionalized hydrogel system, which provided cell-cell adhesion cue to modulate intercellular communications to significantly promote the formation of active neural network. The dynamic assembly of N-cadherin at cell membrane-hydrogel interface driven by adhered cells occurred at a timescale of minutes, facilitating the reshaping of membrane protrusions to initiate intercellular adherens junctions and modulate long-term cell-cell communications. Focusing on the mechanisms, it is associated with Thrombospondin-1 (THBS-1) mediated neural communication and activation of TGF-ß/Smad pathway. Further, this hydrogel system promisingly promoted neurological function recovery in rats following traumatic brain injury. Our study provided the principles of replicating diffusive cell adhesion molecules to mediate cell-cell adhesion in hydrogels, which may have broad applications in the development of engineered biomaterials aimed at modulating cell fates in regeneration of various tissues. Overall design: To reveal the molecular mechanism of cell-cell adhesion cue in hydrogel promoting neural growth, primary cells from cerebral cortex were cultured on hydrogels for 24 hours, respectively. The differentally expressed genes were screened by RNA sequencing. The transcriptome sequencing studies were performed by deep sequencing, using Illumina NovaSeq 6000.