Laminin-Modified Porous GelMA Microspheres Sustain a Pro-Neurogenic Niche for Neural Stem Cells Transplantation in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) remains a major challenge due to the poor regenerative capacity of the central nervous system. Although neural stem cells (NSCs) transplant may serve as a promising therapeutic approach, the aberrant microenvironment in the injured spinal cord leads to low survival and improper differentiation of the NSCs, significantly hindering neurofunctional recovery. In this study, we design laminin-modified porous gelatin methacryloyl (Lam-pGelMA) microspheres to create a biomimetic, 3D niche that sustains NSCs survival, promotes neuronal differentiation, and counters adverse neuroinflammation. In vitro, Lam-pGelMA microspheres substantially enhance NSCs adhesion and proliferation. Additionally, under oxygen-glucose deprivation, these microspheres improve NSCs viability and induce robust differentiation into neurons and oligodendrocytes, primarily through extracellular matrix receptor interactions and activation of the PI3K-Akt pathway. In a rat compression SCI model, NSCs loaded Lam-pGelMA microspheres are injected into the lesion site one week after injury. In vivo, NSCs loaded Lam-pGelMA microspheres significantly reduce tissue distortion, attenuate neuroinflammation, promote endogenous neurogenesis and facilitate functional recovery. Mechanistic studies reveal that NSCs co-transplanted with Lam-pGelMA microspheres exhibit enhanced survival and efficient neuronal differentiation. Overall, these findings highlight the potential of Lam-pGelMA microspheres as a novel cell delivery platform for NSCs-based therapies in SCI repair.