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-β/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.细胞间粘附（cell-cell adhesion）对于维持生物体的细胞功能与组织结构完整性至关重要。然而，在生物材料中尚未能有效复现细胞间粘附信号，且介导神经再生增强的细胞间粘附相关机制仍未得到充分探索。本研究构建了一种扩散型N-钙粘蛋白（N-cadherin）功能化水凝胶系统，该系统可提供细胞间粘附信号以调控细胞间通讯，进而显著促进活性神经网络的形成。粘附细胞驱动下，N-钙粘蛋白在细胞膜-水凝胶界面发生动态组装，该过程耗时仅数分钟，可促进膜突起重塑以启动细胞间粘着连接（adherens junctions）的形成，并调控长期细胞间通讯。针对其作用机制，该系统与血小板反应蛋白-1（Thrombospondin-1，THBS-1）介导的神经通讯以及转化生长因子-β/Smad（TGF-β/Smad）信号通路的激活密切相关。此外，该水凝胶系统可有效促进创伤性脑损伤模型大鼠的神经功能恢复，展现出良好的应用潜力。本研究阐明了在水凝胶中复现扩散型细胞粘附分子以介导细胞间粘附的核心原理，该策略在开发用于调控多种组织再生过程中细胞命运的工程化生物材料领域具有广阔的应用前景。