Fas Receptor Modulates Lineage Commitment and Stemness of Mouse Neural Stem Cells

Abstract

Although transplanted neural stem/progenitor cells (NPCs) can ameliorate disease course in animal models of central nervous system inflammatory and neurodegenerative diseases, little is known about the regulation of NPC differentiation and proliferation. The Fas receptor, a member of the tumor necrosis factor (TNF) superfamily, has recently been shown to be important in NPC survival and immunoregulatory functions. We were interested in further investigating this system utilizing NPCs isolated from Fas-deficient (lpr) mutant mice. We found that lpr NPCs have increased survival and decreased proliferation. Additionally, RT-qPCR, confocal microscopy, and flow cytometry surface staining reveal that lpr NPCs have a significantly more robust differentiation to neuronal and oligoprogenitor cell lineages as compared to wild-type (wt) NPCs. These effects correlated with an upregulation of three of the major fate specification modulators in lpr NPCs: sonic hedgehog (Shh), slit homolog 2 (Slit2), and noggin. These data indicate Fas plays an important role in determining the stemness and differentiation fate of NPCs. Additionally, our research reveals a novel connection between Fas and major modulators of NPC differentiation – Shh, Noggin, and Slit2. This is the first indication of a possible link between Fas and these particular signaling molecules that control neuronal fate specification. Therefore, our results suggest Fas is a novel target for controlling the development of neurons versus mature oligodendrocytes.