Development of molecular imaging system to visualize the processing of CD44 in NG2 cell, and its application to stem cell therapy for multiple sclerosis

Development of molecular imaging system to visualize the processing of CD44 in NG2 cell, and its application to stem cell therapy for multiple sclerosis

Development of molecular imaging system to visualize the processing of CD44 in NG2 cell, and its application to stem cell therapy for multiple sclerosis

Abstract

Recent investigation has revealed that glial cell lineage is not simply classified into three types of cells, astrocyte, oligodendrocyte and microglia, as classically described, but another new population, NG2 cell, should be taken into consideration as a member of glial family. Among functions of NG2 cells shown by previous physiological studies, modification of synaptic transmission, generation of new neuron and oligodendrocyte to repair the injured CNS, and regulation neural functions via neuron-NG2 cell synapse are included, but molecular machinery underlying various functions of NG2 cell is still to be solved. Interestingly, prominent evidence demonstrated the high expression level of CD44 in NG2 cell. CD44 is a membrane protein, which is cleaved by γ-secretase related to the etiology of Alzheimer’s disease. Because the involvement of CD44 in NG2 cell’s function has not been appreciated yet, the present study investigated how CD44 works to accomplish multiple roles of NG2 cell by developing molecular imaging system on the basis of FRET technology, where functional fluorescent probe switches on and emits fluorescence upon the shedding of membranous CD44 by γ-secretase. Utilizing the newly developed imaging method, the generation of intracellular fragment of CD44 could be visualized under fluorescent microscope, and the present results demonstrated that the activation of γ-seceretase induced astrocytic differentiation of NG2 cell, whereas the inhibition of γ-secretase arrested NG2 cells in immature status. These data propose the possibility that CD44 should be therapeutic target to treat demyelinating disorders such as multiple sclerosis, in which immature NG2 cells are accumulated in the affected brain. Further investigations are required to identify the transcriptional target of the intracellular domain of CD44 in NG2 cell, and also to appreciate the precise implication of γ-secretase in glial development and interaction with neuron.

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