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While it is known that mechanical dynamics are influential in neural differentiation for critical processes like neurogenesis or neurodegeneration, studies on neural stem cell therapies usually focus on biochemical interactions rather than mechanical aspects, frequently resulting in low efficacy and unfulfilled potential. Therefore, current studies are attempting to elucidate the effect of mechanical stimulus on neural performance using conventional two-dimensional (2D) planar substrates. Yet, these 2D substrates fail to capture the defining three-dimensional (3D) characteristics of the in vivo neural stem cell environment.To complete this research gap, we synthesized a series of soft and elastic 3D hydrogels to mimic the neural tissue mechanical environment for 3D cell culture, using long-chain polyethylene glycol diacrylate (PEGDA) and gelatin-methacryloyl (GelMA). By varying the concentration of the polymer, we obtained biomimicking hydrogels with a tensile modulus as low as 10 kPa and a compressive modulus as low as 0.8 kPa. The in vitro results demonstrated that GelMA-PEGDA hydrogels have the high biocompatibility required to support neural cell growth, proliferation, and differentiation, as well as neurite outgrowth. We then studied the effect of mechanical stretching on the behaviors of neural cells and observed that mechanical stretching could significantly enhance neurite extension and axon elongation. In addition, the neurites were more directionally oriented to the stretching direction. Immunocytochemistry and relative gene expression data also suggested that mechanical tension could upregulate the expression of neural differentiation protein and genes, including GFAP and βIII-Tubulin. Overall, this study shows that in addition to the specific mechanical properties of GelMA-PEGDA that improve neural differentiation towards specific lineages, hydrogel stretching is also a potentially attractive strategy to improve the therapeutic outcomes of neural stem cell therapies.

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