A Synthetic Small Molecule That Induces Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells

摘要

Neural stem/progenitor cells have been identified in several regions of the adult brain, including the subventricular zone and the dentate gyrus of the hippocampus. They are multipotent in vitro (i.e., they can give arise to neurons, astrocytes, and oligodendrocytes) and have been shown to contribute to neurogenesis in adulthood.[1], [2] The discovery of neural stem/progenitor cells (NPCs) in the adult central nervous system has created considerable interest in the development of stem-cell-based therapies for neurodegenerative disease.[2]-[4] However, the molecular mechanisms that underlie stem-cell-fate specification are still poorly understood, and we lack robust and selective methods to control the differentiation programs of NPCs. Although several agents, including retinoic acid (RA),[1] leukemia inhibitory factor (LIF),[5] and insulin-like growth factor-1 (IGF-1),[6] have been found to direct neuronal, astroglial, and oligodendrocytic differentiation, they either are pleiotropic or have poor in vivo activities. Moreover, relatively little is known about the endogenous molecules that control stem-cell fate. Consequently, the generation of small molecules that can direct differentiation of adult NPCs could provide useful chemical tools to probe signaling pathways that control neuronal specification and could ultimately facilitate therapeutic application of NPCs. Herein, we report the identification and preliminary characterization of a novel small molecule, neuropathiazol, that selectively induces neuronal differentiation of multipotent hippocampal neural progenitor cells.