Cellular remodeling of the matrix has recently emerged as a key factor in promoting neural differentiation. Most strategies to manipulate matrix remodeling focus on proteolytically cleavable cross-linkers, leading to changes in tethered biochemical signaling and matrix properties. Using peptides that are not the direct target of enzymatic degradation will likely reduce changes in the matrix and improve control of biological behavior. In this study, laminin-derived peptides, IKVAV and LRE, tethered to independent sites in hyaluronic acid matrices using Michael addition and strain-promoted azide-alkyne cycloaddition are sufficient to manipulate hyaluronic acid degradation, gelatinase expression, and protease expression, while promoting neurite extension through matrix metalloprotease-dependent mechanisms in mouse embryonic stem cells encapsulated in hyaluronic acid matrices using an oxidation-reduction reaction initiated gelation. This study provides the foundation for a new strategy to stimulate matrix remodeling that is not dependent on enzymatic cleavage targets.