Hydrogel encapsulated stem cells facilitate successful repair after spinal cord injury in rats and monkeys

Abstract

Abstract Promoting axonal regeneration to form nascent circuits after spinal cord injury (SCI) is a considerable challenge. While cell-based transplantation is considered a top candidate for SCI therapeutics, limited anatomical structure repair and slight functional recovery have prevented translation to the clinic. Here we develop a biodegradable hydrogel to encapsulate GMP-produced human neuroepithelial stem cells (NESCs) and mesenchymal stem cells (MSCs) individually or in combination. When grafted into completely transected SCI rats, hydrogel-encapsulated stem cells elicit robust endogenous axonal regrowth across lesions to reestablish functional connections, and rats recover both locomotor and bladder function. Combined delivery of NESCs and MSCs (NESC + MSC) brings the best therapeutic recovery. In this condition, regenerating axons adopt a linear axonal alignment, similar to an intact spinal cord. When MSC + NESC are implanted into quarter-sectioned SCI adult monkeys (Macaca mulatta), behavior, electrophysiology, diffusion tensor imaging and histopathology analyses demonstrate robust axonal regeneration to form nascent circuits accompanied by substantial motor functional recovery of complete paralyzed limbs to walk with weight. Mechanistically, hydrogel-encapsulated stem cells activate endogenous axon regeneration, decrease inflammation, and reduce activated microglia and glial scar formation. These preclinical findings support translation of this method to human SCI repair.