Cell-adaptable dynamic hydrogel reinforced with stem cells improves the functional repair of spinal cord injury by alleviating neuroinflammation

ABSTRACT Spinal cord injury (SCI) is one of the most challenging clinical issues. It is characterized by the disruption of neural circuitry and connectivity, resulting in neurological disability. Adipose-derived stem cells (ADSCs) serve as a promising source of therapeutic cells for SCI treatment. However, the therapeutic outcomes of direct ADSCs transplantation are limited in the presence of an inflammatory microenvironment. Herein, a cell-adaptable neurogenic (CaNeu) hydrogel was developed as a delivery vehicle for ADSCs to promote neuronal regeneration after SCI. The dynamic network of CaNeu hydrogel loaded with ADSCs provides a cell-infiltratable matrix that enhances axonal growth and eventually leads to improved motor evoked potential, hindlimb strength, and coordination of complete spinal cord transection in rats. Furthermore, the CaNeu hydrogel also establishes an anti-inflammatory microenvironment by inducing a shift in the polarization of the recruited macrophages toward the pro-regeneration (M2) phenotype. Our study showed that the CaNeu-hydrogel‒mediated ADSCs delivery resulted in significantly suppressed neuroinflammation and apoptosis, and that this phenomenon involved the PI3K/Akt signaling pathway. Our findings indicate that the CaNeu hydrogel is a valuable delivery vehicle to assist stem cell therapy for SCI, providing a promising strategy for central nervous system diseases.