Abstract
There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33–60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate.
Highlights
The discovery of adult neurogenesis and adult human neural stem-like cells in the brain has opened a novel field of research aiming to utilise these cells as sources of repair in the treatment of degenerative disorders, such as Parkinson’s and Alzheimer’s disease [1]. ahNSCs can be isolated from the hippocampus or subventricular zone of the lateral ventricles (SVZ) [2,3,4,5,6]
This study represents the first global transcriptional profile of ahNSCs from the subventricular zone enriched as neurospheres
From 12 individuals, including samples for microarrays, quantitative PCR (qPCR) and immunofluorescence, we present the genes and pathways that are highly upregulated in ahNSCs compared to levels in normal brain tissue
Summary
The discovery of adult neurogenesis and adult human neural stem-like cells (ahNSC) in the brain has opened a novel field of research aiming to utilise these cells as sources of repair in the treatment of degenerative disorders, such as Parkinson’s and Alzheimer’s disease [1]. ahNSCs can be isolated from the hippocampus or subventricular zone of the lateral ventricles (SVZ) [2,3,4,5,6]. The discovery of adult neurogenesis and adult human neural stem-like cells (ahNSC) in the brain has opened a novel field of research aiming to utilise these cells as sources of repair in the treatment of degenerative disorders, such as Parkinson’s and Alzheimer’s disease [1]. Despite the great interest in and potential of ahNSCs, there is still limited knowledge regarding the hierarchy of stem- and progenitor cells in the human brain. This is in contrast to research on the hematopoietic cell lineage, where a detailed set of surface markers and transcription factors have been identified [8, 9]. Similar approaches have been used in attempts to identify markers that prospectively distinguish adult NSCs from neural progenitors in rodents. Studies of NSCs from the adult human brain are still few and far between, GFAPd positive cells expressing the surface receptor NGFR was recently suggested as a markers of ahNSCs [11]
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