Functionalized scaffolds of shorter self-assembling peptides containing MMP-2 cleavable motif promote fibroblast proliferation and significantly accelerate 3-D cell migration independent of scaffold stiffness

Abstract

The functionalization of self-assembling peptide scaffolds with biologically active motifs presents many possibilities for the design of synthetic biological materials for 3D cell culture, reparative, regenerative medicine and tissue engineering. We here report the development of short self-assembling peptide scaffolds designed especially for cell migration. We designed self-assembling peptide scaffolds VEVK9 (Ac-VEVKVEVKV-CONH₂) and VEVK12 (Ac-VEVKVEVKVEVK-CONH₂) and modified variants of these peptides directly coupled to short biologically active motifs. These motifs include two-unit RGD binding units (PRGDSGYRGDS), cell adhesion sequences of laminin (YIGSR and IKVAV) and a Matrix metalloproteinase-2 (MMP-2) cleavable sequence (PVGLIG). We show here that the peptide scaffolds functionalized with these cell adhesion motifs significantly promoted proliferation of periodontal ligament fibroblasts. Moreover, when combined with the MMP-2 cleavable motifs, the peptide scaffolds significantly accelerated the fibroblasts' migration independent of scaffold stiffness. Our results suggest that the interaction between integrin receptors of fibroblasts and cell adhesion motifs of the scaffolds stimulated MMP-2 production from the fibroblasts to accelerate proteolytic cell migration in the similar manner as natural extracellular matrix. These peptide scaffolds may be useful in tissue engineering and regenerative medicine including periodontal tissue reconstruction.