Microglia are resident immune cells in the central nervous system (CNS) that play vital roles in CNS development, homeostasis and disease pathogenesis. Genetic defects in microglia lead to microglial dysfunction, which in turn leads to neurological disorders. The correction of the specific genetic defects in microglia in these disorders can lead to therapeutic effects. Traditional genetic defect correction approaches are dependent on viral vector-based genetic defect corrections. However, the viruses used in these approaches, including adeno-associated viruses, lentiviruses and retroviruses, do not primarily target microglia; therefore, viral vector-based genetic defect corrections are ineffective in microglia. Microglia replacement is a novel approach to correct microglial genetic defects via replacing microglia of genetic defects with allogenic healthy microglia. In this paper, we systematically review the history, rationale and therapeutic perspectives of microglia replacement, which would be a novel strategy for treating CNS disorders.

Microglia are the specialized macrophages of the central nervous system and play an important role in neural circuit development, modulating neurotransmission, and maintaining brain homeostasis. Microglia in normal brain is quiescent and show ramified morphology with numerous branching processes. They constantly survey their surrounding microenvironment through the extension and retraction of their processes and interact with neurons, astrocytes, and blood vessels using these processes. Microglia respond quickly to any pathological event in the brain by assuming ameboid morphology devoid of branching processes and restore homeostasis. However, when there is chronic inflammation, microglia may lose their homeostatic functions and secrete various proinflammatory cytokines and mediators that initiate neural dysfunction and neurodegeneration. In this article, we review the role of microglia in the normal brain and in various pathological brain conditions, such as Alzheimer\'s disease and multiple sclerosis. We describe strategies to manipulate microglia, focusing on depletion, repopulation, and replacement, and we discuss their therapeutic potential.