Promoting 3D neuronal differentiation in hydrogel for spinal cord regeneration

Spinal cord injury (SCI) affects millions of people worldwide, and results in the loss of neurons and limited recovery of functions. Bone mesenchymal stem cells (BMSCs) and neural stem cells (NSCs) can proliferate or differentiate into other specific cell types. These cells represent potential treatments for SCIs. However, recent studies have shown that NSCs mainly differentiate into astrocytes, rather than neurons, in the microenvironment of an SCI. BMSCs have been reported to promote neuronal differentiation of NSCs and reduce the formation of astrocytes. Furthermore, three-dimensional (3D) gelatin methacryloyl (GelMA) provides superior mechanical properties and functional characteristics for cell proliferation, migration, and differentiation. In this study, we proposed a functional scaffold developed by loading BMSCs and NSCs into 3D GelMA hydrogel. BMSCs and NSCs that were photo-encapsulated in the 3D GelMA hydrogel survived and demonstrated good proliferation in vitro. The NSCs differentiated more toward neurons and oligodendrocytes than toward astrocytes, a phenomenon more noticeable in low-modulus hydrogels. When functional hydrogel scaffolds, loaded with BMSCs and NSCs, were implanted into the hemisection site of the rat spinal cord, they could significantly promote motor function recovery and neuronal differentiation, and decrease glial scarring, fibrotic scarring, and inflammatory responses. The immense therapeutic potential of this system to promote axonal regeneration was thereby demonstrated. Taken together, loading of the GelMA scaffold with BMSCs and NSCs is a promising therapeutic strategy to trigger functional regeneration of the spinal cord.