Abstract
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, this issue is tackled by delivery through silk-collagen protein hydrogels that are stiffness-matched, stress-relaxing, and shear-thinning. The mechanically-tuned hydrogels protect NSC reprogrammed from fibroblasts (iNSC) initially from injection shear-stress, and enhance long-term survival over 12 weeks. Hydrogel-iNSC treatment alleviates neural inflammation, with reduced inflammatory cells and lesions than NSC-only. The iNSC migrate from the hydrogel into surrounding tissues, secrete up-regulated neurotrophic factors, and differentiate into neural cell subtypes, forming synapses. More serotonergic axons are observed in the lesion cavity, and locomotor functions are improved in hydrogel-iNSC than in iNSC-only. This study highlights the ability of mechanically-tuned protein hydrogels to protect iNSC from the injection stress and severe inflammatory environment, allowing them to differentiate and function to recover the injured spinal cord.