EMSCs Build an All‐in‐One Niche via Cell–Cell Lipid Raft Assembly for Promoted Neuronal but Suppressed Astroglial Differentiation of Neural Stem Cells

Abstract The therapeutic efficiency of allogenic/intrinsic neural stem cells (NSCs) after spinal cord injury is severely compromised because the hostile niche at the lesion site incurs massive astroglial but not neuronal differentiation of NSCs. Although many attempts are made to reconstruct a permissive niche for nerve regeneration, solely using a living cell material to build an all‐in‐one, multifunctional, permissive niche for promoting neuronal while inhibiting astroglial differentiation of NSCs is not reported. Here, ectomesenchymal stem cells (EMSCs) are reported to serve as a living, smart material that creates a permissive, all‐in‐one niche which provides neurotrophic factors, extracellular matrix molecules, cell–cell contact, and favorable substrate stiffness for directing NSC differentiation. Interestingly, in this all‐in‐one niche, a corresponding all‐in‐one signal‐sensing platform is assembled through recruiting various niche signaling molecules into lipid rafts for promoting neuronal differentiation of NSCs, and meanwhile, inhibiting astrocyte overproliferation through the connexin43/YAP/14‐3‐3θ pathway. In vivo studies confirm that EMSCs can promote intrinsic NSC neuronal differentiation and domesticating astrocyte behaviors for nerve regeneration. Collectively, this study represents an all‐in‐one niche created by a single‐cell material—EMSCs for directing NSC differentiation.