Long‐Term Effects of Xenotransplantation of Human Enteric Glia in an Immunocompetent Rat Model of Acute Brain Injury

Acute brain injuries are characterized by extensive tissue damage, resulting in functional deficits in patients. The capacity of nerve tissue to self-regenerate is insufficient, thus therapies based on exogenous cells are urgently needed. Human enteric glia (EG) have interesting intrinsic properties that make them a valuable candidate for regenerative medicine. Malonate-induced acute brain injury is performed in the motor cortex of female rats, causing extensive tissue damage and long-lasting sensorimotor deficits. Human EG are isolated, expanded and administered intranasally in awake immunocompetent rats. To determine the long-term safety and efficacy of human EG treatment, longitudinal evaluation of sensorimotor function, post-mortem tissue analysis and the fate of human EG are assessed thirty-six-weeks post-injury. Transplanted human EG are well tolerated in immunocompetent rats. Thirty-six-weeks post-injury, intranasally delivered human EG are detected in the rat brain, mainly in the injured motor cortex. They engraft and integrate with the host tissue, and enhance endogenous angiogenesis and neurogenesis. Notably, mature neurons derived from human EG are found and appear enveloped by oligodendrocytes, form synaptic connections with the host tissue, and are differentiated. This is the first study demonstrating the feasibility, safety and efficacy of intranasal administration of human EG for treatment of brain injury.