视神经损伤

    In vivo direct reprogramming as a therapeutic strategy for brain and retina repair
  • Figure 1|Direct neural reprogramming in different locations by manipulation of the same genes’ expression.

    Generation of the appropriate neuronal subtypes corresponding to particular regions in the brain and retina is crucial for neuronal repair and functional recovery. A recent study showed that combined expression of Neurog2 and Nurr1 in upper- or lower-layer astrocytes in the cortex induces reprogramming into different subtypes of iN cells, namely, Cux1-positive upper-layer or Ctip2-positive lower-layer neurons (Mattugini et al., 2019), respectively. Furthermore, Ptbp1 converts two different types of brain cells, striatal astrocytes and Müller glia, into glutamatergic neuron-like cells and retinal ganglion-like cells, respectively (Zhou et al., 2020) (Figure 1). These facts suggest that extrinsic signals from the surrounding environment determine the effects of neuronal reprogramming factors and subsequent specification of neuronal subtypes. Neuronal reprogramming has also been reported to be affected by epigenetic signatures of the original cells. For instance, in the conversion of mouse embryonic fibroblasts (MEFs) to neurons, there is a trivalent chromatin state, composed of two marks associated with an active state (H3K4me1 and acetylation of histone H3 at lysine 27 [H3K27ac]) and a repressive mark (H3K9me3), on many Ascl1-bound loci (Wapinski et al., 2013). NeuroD1 can efficiently reprogram microglia into neurons, but Ascl1 cannot (Matsuda et al., 2019), probably because Ascl1 target sites lack such a trivalent state in microglia. Furthermore, non-reactive astrocytes cannot be reprogrammed by NeuroD1, whereas oligodendrocytes can (Matsuda et al., 2019). This is due to the fact that oligodendrocytes, but not non-reactive astrocytes, have a bivalent signature (H3K4me3 and H3K27me3) in NeuroD1-bound loci around neuronal genes (Matsuda et al., 2019). Recent studies have shown that astrocytes in the corpus callosum cannot be reprogrammed into neurons by expression of either NeuroD1 or the combination of Neurog2 and Nurr1, whereas astrocytes in the cortex can (as described above), implying that different epigenetic signatures of astrocytes in distinct brain regions affect reprogramming efficiency. All of these facts taken together indicate that the epigenetic profiles in the original cells affect reprogramming efficiency, but once the original cells are committed to the neuronal lineage by reprogramming factors, they may become suitable neuronal subtypes in response to the surrounding environment. Further investigation is therefore warranted to examine whether pan-neuronal transcription factors such as NeuroD1 or Neurog2 can convert microglia into appropriate neuronal subtypes in each region in the brain and retina according to the external milieu (Figure 1). 

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  • 发布日期: 2021-03-20  浏览: 586
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