Fate plasticity of adult hippocampal progenitors: biological relevance and therapeutic use

Abstract

Adult hippocampal stem/progenitor cells (AHPs) continuously give rise to new neurons throughout life, which might be an important determinant of hippocampus-dependent function. Strikingly, the fate potential of AHPs is not restricted to the neuronal lineage because AHPs can be genetically induced to generate oligodendrocytes within their in vivo niche by AHP-specific ectopic expression of the basic-helix-loop-helix (bHLH) transcription factor achaete-scute complex-like 1 (ASCL1). Fate plasticity of AHPs is controlled by cell-autonomous and also niche-dependent mechanisms. Here, we discuss the biological importance and potential therapeutic applications of retained fate plasticity of AHPs in the adult mammalian brain in addition to the future scientific inquiries indicated by this finding.

Figure 1

Ascl1 instructs AHPs to adopt an oligodendrocytic fate. (a) Newborn cells differentiate predominantly into granule cells in the adult hippocampus. Shown are retrovirus-labeled cells four weeks after injection of a green fluorescent protein (GFP)-expressing retrovirus (green). Retrovirus-mediated Ascl1 expression results in fate change (right panels; inset shows high-power view of an Ascl1-expressing newborn cell). (b) A fraction of Ascl1-induced, GFP-labeled oligodendrocytes (green) expresses myelin basic protein (MBP; red) wrapping around axonal processes (neurofilament 200 kD protein, blue). Left panels show single channels for GFP and MBP pointing toward GFP/MBP-co-labeled cells (red arrowheads in left panels; white arrowheads in right panels). (c) Ascl1-expressing cells have ultrastructural features of oligodendrocytic cells such as heterochromatin, a large nucleus and a large Golgi apparatus. For high-power confocal images and additional electron microscopy images supporting evidence for myelinating Ascl1-expressing cells, please refer to Ref. [10]. Abbreviations: GCL, granule cell layer.

Figure 2

Context-dependent fate specification induced by Ascl1. (a) Dividing AHPs that are located in the inner border of the granule cell layer expressing certain transcription factors such as SOX2 and TLX almost exclusively generate excitatory granule cells under control conditions (i). Even though direct evidence is scant, a sequence of bHLH and proneural transcription factors, such as neurogenin 2 (NGN2), neurogenic differentiation 1 (NeuroD1) and prospero homeobox 1 (PROX1), is thought to be required for proper neuronal differentiation. AHP-specific expression of Ascl1 within the in vivo niche redirects the fate of the progeny from a neuronal to an oligodendrocytic lineage (ii). This fate specification is accompanied by oligodendrocyte lineage transcription factor 2 (OLIG2) expression but potentially involves other transcription factors that are induced in the course of fate specification. (b) The effect of ASCL1 is context dependent because isolated AHPs differentiate into neuronal cells and not oligodendrocytes when challenged with Ascl1 in the culture dish; this is similar to the overexpression of proneural genes such as NGN2 and NeuroD1. The distinct response to Ascl1 in vitro and in vivo indicates context-dependent effects of ASCL1 that are specific to the endogenous niche of AHPs, which could be explained by factors expressed within the dentate niche or alterations in neural stem/progenitors upon isolation and growth factor exposure