Designing aromatic N-cadherin mimetic short-peptide-based bioactive scaffolds for controlling cellular behaviour

Abstract

The development of suitable biomaterials is one of the key factors responsible for the success of the tissue-engineering field. Recently, significant effort has been devoted to the design of biomimetic materials that can elicit specific cellular responses and direct new tissue formation mediated by bioactive peptides. The success of the design principle of such biomimetic scaffolds is mainly related to the cell–extracellular matrix (ECM) interactions, whereas cell–cell interactions also play a vital role in cell survival, neurite outgrowth, attachment, migration, differentiation, and proliferation. Hence, an ideal strategy to improve cell–cell interactions would rely on the judicious incorporation of a bioactive motif in the designer scaffold. In this way, we explored for the first time the primary functional pentapeptide sequence of the N-cadherin protein, HAVDI, which is known to be involved in cell–cell interactions. We have formulated the shortest N-cadherin mimetic peptide sequence utilizing a minimalistic approach. Furthermore, we employed a classical molecular self-assembly strategy through rational modification of the basic pentapeptide motif of N-cadherin, i.e. HAVDI, using Fmoc and Nap aromatic moieties to modify the N-terminal end. The designed N-cadherin mimetic peptides, Fmoc-HAVDI and Nap-HAVDI, self-assembled to form a nanofibrous network resulting in a bioactive peptide hydrogel at physiological pH. The nanofibrous network of the pentapeptide hydrogels resembles the topology of the natural ECM. Furthermore, the mechanical strength of the gels also matches that of the native ECM of neural cells. Interestingly, both the N-cadherin mimetic peptide hydrogels supported cell adhesion and proliferation of the neural and non-neural cell lines, highlighting the diversity of these peptidic scaffolds. Further, the cultured neural and non-neural cells on the bioactive scaffolds showed normal expression of β-III tubulin and actin, respectively. The cellular response was compromised in control peptides, which further establishes the significance of the bioactive motifs towards controlling the cellular behaviour. Our study indicated that our designer N-cadherin-based peptidic hydrogels mimic the structural as well as the physical properties of the native ECM, which has been further reflected in the functional attributes offered by these scaffolds, and thus offer a suitable bioactive domain for further use as a next-generation material in tissue-engineering applications.