脊髓损伤
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Figure 1 ｜ Predicted difference in neuronal subtypes of reprogrammed neurons from reactive astrocytes by NeuroD1 and miRNAs in the injured spinal cord.
MicroRNAs (miRNAs) are endogenously derived, short non-coding RNAs that regulate gene expression posttranscriptionally (Bartel, 2004). MiRNAs are crucial to differentiation of neural cell types during CNS development (Rajman and Schratt, 2017), as well as pathological processes after neural injury (Ambros, 2004; Alvarez-Garcia and Miska, 2005; Christensen and Schratt, 2009) including SCI (Liu et al., 2009; Yan et al., 2012; Nieto-Diaz et al., 2014). MiRNAs are small and chemically modifiable, which make them ideal candidates for therapy. Modifications such as cholesterol linkage at the 3′ end, 2′-O-methylation, and locked-nucleicacid significantly increase their penetration, stability, and efficacy (Yan et al., 2012). A variety of techniques have been developed over the years to target the CNS with high efficiency and cellular specificity (van Rooij and Kauppinen, 2014; Wen, 2016). In fact, some modified miRNAs are already in clinical trials (Hydbring and Badalian-Very, 2013; Simonson and Das, 2015). The idea of using miRNAs to perform neuronal reprogramming has been developed. For example, miR-124 and miR-9 together are able to convert fibroblasts into neurons in culture (Yoo et al., 2011). Whether miRNAs can reprogram glial cells into neurons in the injured spinal cord needs to be tested in the future. NeuroD1-converted neurons are mostly glutamatergic subtype in the brain and spinal cord (Guo et al., 2014; Puls et al., 2020). Although the underlying mechanism is unclear, NeuroD1 as a basic helixloop-helix transcription factor could play an instructive role by turning on neuronal genes (Figure 1A) (Boutin et al., 2010). However, miRNAs possess a different mechanism of action by mainly inhibiting translation of the target genes (Lim et al., 2005; Conaco et al., 2006). Therefore, forced expression of miRNAs may play a permissive, rather than instructive, role during astrocyte-to-neuron conversion, and that the fate of neuronal subtype of miRNA-converted neurons may more likely be determined by the local environment (Figure 1B). For example, the region-specific environment may affect subtype determination of newly converted neurons in the spinal cord (i.e., dorsal horn, enriched in GABAergic interneurons; and ventral horn, enriched in cholinergic motor neurons) (Figure 1B). If this is true, miRNA-mediated neuronal conversion may have the advantage of generating different neuronal subtypes in different spinal cord regions, which is important for functional repair after SCI.