Glia in tissue engineering: From biomaterial tools to transplantation.

Glia are imperative in nearly every function of the nervous system, including neurotransmission, neuronal repair, development, immunity, and myelination. Recently, the reparative roles of glia in the central and peripheral nervous systems have been elucidated, suggesting a tremendous potential for these cells as novel treatments to central nervous system disorders. Glial cells often behave as 'double-edged swords' in neuroinflammation, ultimately deciding the life or death of resident cells. Compared to glia, neuronal cells have limited mobility, lack the ability to divide and self-renew, and are generally more delicate. Glia have been candidates for therapeutic use in many successful grafting studies, which have been largely focused on restoring myelin with Schwann cells, olfactory ensheathing glia, and oligodendrocytes with support from astrocytes. However, few therapeutics of this class have succeeded past clinical trials. Several tools and materials are being developed to understand and re-engineer these grafting concepts for greater success, such as extra cellular matrix-based scaffolds, bioactive peptides, biomolecular delivery systems, biomolecular discovery for neuroinflammatory mediation, composite microstructures such as artificial channels for cell trafficking, and graft enhanced electrical stimulation. Furthermore, advances in stem cell-derived cortical/cerebral organoid differentiation protocols have allowed for the generation of patient-derived glia comparable to those acquired from tissues requiring highly invasive procedures or are otherwise inaccessible. However, research on bioengineered tools that manipulate glial cells is nowhere near as comprehensive as that for systems of neurons and neural stem cells. This article explores the therapeutic potential of glia in transplantation with an emphasis on novel bioengineered tools for enhancement of their reparative properties. STATEMENT OF SIGNIFICANCE: Neural glia are responsible for a host of developmental, homeostatic, and reparative roles in the central nervous system but are often a major cause of tissue damage and cellular loss in insults and degenerative pathologies. Most glial grafts have employed Schwann cells for remyelination, but other glial with novel biomaterials have been employed, emphasizing their diverse functionality. Promising strategies have emerged, including neuroimmune mediation of glial scar tissues and facilitated migration and differentiation of stem cells for neural replacement. Herein, a comprehensive review of biomaterial tools for glia in transplantation is presented, highlighting Schwann cells, astrocytes, olfactory ensheating glia, oligodendrocytes, microglia, and ependymal cells.