Delivery of Induced Neural Stem Cells Through Mechano-tuned Silk-collagen Hydrogels

https://onlinelibrary.wiley.com/doi/10.1002/adhm.202201720

Neural stem cells (NSC) have tremendous potential for therapeutic regeneration of diseased or traumatized neural tissues, including injured spinal cord. However, transplanted NSC suffer from low cell survival and uncontrolled differentiation, limiting in vivo efficacy. Here we tackle this issue by delivery through silk-collagen protein hydrogels that are stiffness-matched, stress-relaxing and shear-thinning. The mechanically-tuned hydrogels protected NSC reprogrammed from fibroblasts initially from injection shear-stress, and enhanced long-term survival over 12 weeks. Hydrogel-NSC treatment alleviated neural inflammation, with reduced inflammatory cells and lesions than NSC-only. The NSC migrated from the hydrogel into surrounding tissues, secreted up-regulated neurotrophic factors, and differentiated into neural cell subtypes, forming synapses. More serotonergic axons were observed in the lesion cavity, and locomotor functions were improved in hydrogel-NSC than in NSC-only. This study highlights the ability of mechanically-tuned protein hydrogels to protect NSC from the injection stress and severe inflammatory environment, allowing them to differentiate and function to recover injured spinal cord.