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.
Highlights
There is a critical need for developing direct neuroregenerative therapies for demyelinating diseases, including multiple sclerosis (MS)
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 Neural stem/progenitor cell (NPC) differentiation and proliferation
In order to confirm that lpr NPCs lack Fas, we stained NPCs with a Fas-specific phycoerythrin (PE)-conjugated antibody
Summary
There is a critical need for developing direct neuroregenerative therapies for demyelinating diseases, including multiple sclerosis (MS). MS treatments are limited to peripheral immunoregulation and are ineffective in later, progressively neurodegenerative stages of the disease. Neural stem/progenitor cell (NPC) therapies offer a potentially powerful treatment approach for the chronic neurodegeneration that occurs in these later stages [1]. The two main experimental modalities for NPC therapy are exogenous transplantation and activation/recruitment of the endogenous adult NPC compartment [2]. Differentiation and integration of NPCs to enhance central nervous system (CNS) repair is the most sought after outcome. Though exogenous application of NPC has shown significant recovery in animal models of MS (experimental autoimmune encephalomyelitis), the functional integration and terminal differentiation of transplanted cells is extremely rare [1, 3]. The signaling pathways that control NPC survival and differentiation are not well understood; elucidating these complex pathways is paramount for advancing this therapeutic approach
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