The coordination between neurogenesis and angiogenesis plays an important role in nerve tissue development and regeneration. Recently, using bioactive materials to drive neurogenic and angiogenic responses has gained increasing attention. Understanding the neurovascular link between regulatory cues offers valuable insight into the mechanisms underlying nerve regeneration and the design of new bioactive materials. In this study, we utilized a dual-functionalized peptide nanofiber hydrogel presenting the brain- derived neurotrophic factor and vascular endothelial growth factor mimetic peptides RGIDKRHWNSQ (RGI) and KLTWQELYQLKYKGI (KLT) to construct an artificial neurovascular microenvironment. The dual-functionalized peptide nanofiber hydrogel enhanced the neurite outgrowth of pheochromocytoma (PC12) cells and tube-like structures formation of human umbilical vein endothelial cells (HUVECs) in vitro, and promoted rapid lesion infiltration of neural and vascular cells in a rat brain injury model. Using indirect co-culture models, we found that the dual-functionalized peptide hydrogel effectively mediated neurovascular crosstalk by regulating secretion of paracrine factors from PC12 cells and HUVECs. When the two cells types were directly co-cultured on the dual-functionalized peptide hydrogel, the efficiency of cell–cell communication was enhanced, which further accelerated the differentiation and maturation of PC12 cells with an increased number of pseudopodia and spread morphology, and HUVECs tube-like structure formation. In summary, the dual-functionalized peptide nanofiber hydrogel successfully formed an artificial neurovascular niche to directly regulate the behaviors of neural and vascular cells and promote their neurovascular crosstalk through paracrine signaling and direct cell–cell contact.
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Nerve guidance conduit (NGC) is a potential alternative to autologous nerve for peripheral nerve regeneration. A promising therapeutic strategy is to modify the nerve guidance conduit intraluminal microenvironment using physical and/or chemical guidance cues. In this study, a neurotrophic peptide-functionalized self-assembling peptide nanofiber hydrogel that could promote PC12 cell adhesion, proliferation, and neuronal differentiation in vitro was prefilled in the lumen of a hollow chitosan tube (hCST) to accelerate axonal regeneration in a rat sciatic nerve defect model. The functionalized self-assembling peptide was developed by introducing a neurotrophic peptide (RGI, RGIDKRHWNSQ) derived from brain-derived neurotrophic factor (BDNF) to the C-terminus of the self-assembling peptide RADA16-I (Ac-(RADA)4-CONH2). Morphological, histological, electrophysiological, and functional analyses demonstrated that the RGI-functionalized, self-assembling, peptide nanofiber hydrogel RAD/RGI could produce a neurotrophic microenvironment that markedly improved axonal regeneration with enhanced re-myelination and motor functional recovery.