NIH Research Festival
Adult neural stem cells (NSCs) are retained in subventricular zone (SVZ) of lateral ventricle, where a specialized niche maintains neurogenesis throughout life. Accumulating evidence suggests that vascular niche signals regulate NSC quiescence and growth. To uncover soluble vascular signals, we used an established NSC culture (neurosphere culture) from adult mouse SVZ cells and tested whether brain microvascular endothelium-derived conditioned medium (bEND3-CM) influence NSC behavior. These experiments demonstrated that the bEND3-CM significantly increased the number of neurospheres but reduced the size of individual neurospheres, suggesting that the bEND3-CM enhance neurosphere-forming potential but suppress NSC growth. Liquid chromatography-mass spectrometry analysis of the bEND3-CM revealed 29 proteins, among which we focused on soluble amyloid precursor protein (sAPP). Like the bEND3-CM, sAPP potentiated the neurosphere-forming activity but suppressed NSC growth. The observation that sAPP decreased proliferating cells but appeared not to affect cell death in Sox2+ NSCs suggests that sAPP serves as a negative regulator for NSC growth. Further in vivo studies deomonstrated that endothelial deletion of App causes a significant increase in the number of BrdU+ label-retaining NSCs in the SVZ, while NSC/astrocyte deletion of App has no detectable effect on the NSC number. Taken together, our results strongly suggest that endothelial APP serves as a vascular niche signal that negatively regulates NSC growth to control the NSC number in the SVZ.
Scientific Focus Area: Stem Cell Biology
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