Chiral Hydrogel\nNerve Conduit Boosts Peripheral Nerve\nRegeneration via Regulation of Schwann Cell Reprogramming

The Schwann cell (SC) is essential in peripheral nerve\nregeneration\nby reprogramming into a stem-like “repair Schwann cell”\n(rSC) phenotype; however, maintaining the rSC stemness remains an\nunmet challenge. Chirality is a fundamental factor controlling cell\nfate, and its potential role in regulation of SC reprogramming has\nlong been ignored and remains poorly understood. Herein, inspired\nby natural chiral components in the SC microenvironment, chiral hydrogel\nnerve conduits are prepared by supramolecular assembly of l/d-phenylalanine derivatives (l/d-Phe)\nin polymeric chitosan-gelatin conduits. Right-handed l-Phe\nfibers within hydrogel conduits maintain the stemness of rSC through\nenhanced stereoselective interaction between collagen IV and l-Phe fibers triggered by collagen IV–Integrin α1β1,\nMAPK, and YAP/TAZ signaling pathways and finally activate the key\nregulator of SC reprogramming, the c-Jun pathway. In the rat model\nof a sciatic nerve defect, the l-Phe hydrogel nerve conduit\nsignificantly enhances nerve regeneration, exhibiting markedly improved\nhistological, electrophysiological, and functional outcomes. The findings\nreveal the chirality-dependent regulation of SC reprogramming in a\npioneering way, offering potential strategies for nerve regeneration\ntherapies.