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Long Non-coding RNAs – The Key to Functional Recovery from Stroke?

Review of “Long noncoding RNA mediates stroke‐induced neurogenesis” from STEM CELLS by Stuart P. Atkinson

Neurogenesis contributes in a limited manner to spontaneous recovery after stroke [1, 2]; however, we may be able to develop novel therapeutic approaches that improve neurological function during recovery through the understanding of the molecular mechanisms controlling basal poststroke neurogenesis. 

Researchers led by Xian Shuang Liu (Henry Ford Hospital, Detroit, MI, USA), and others, had previously underlined the importance of microRNA (miRNA) expression to neurogenesis after stroke [3, 4], and in their new STEM CELLS article [5], the team now describes their exploration of long non-coding RNA (lncRNA) expression in neurogenesis [6, 7] in a stroke model. Fascinatingly, Fan et al. report that the H19 lncRNA, previously reported to be involved in acute stroke‐induced neuroinflammation [8], mediates stroke‐augmented neurogenesis in neural stem cells (NSCs) through a mechanism involving chromatin remodeling proteins.

The authors of this fascinating new study discovered substantially altered lncRNA profiles in rat subventricular zone NSCs following experimental stroke, with H19 representing the most abundant of the 86 upregulated lncRNAs. Interestingly, the inhibition of H19 expression suppressed NSC proliferation and cell survival, blocked neuronal differentiation, influenced the expression of neurogenesis‐related miRNAs, and significantly attenuated spontaneous motor and cognitive function recovery in vivo. H19 loss also prompted the deregulation of genes associated with transcription, apoptosis, proliferation, cell cycle, and responses to hypoxia; however, H19 overexpression substantially reduced the expression of cell cycle‐related genes via interactions with the Enhancer of zeste homolog 2 (Ezh2) histone methyltransferase and the SUZ12 polycomb repressive complex 2 subunit and the elevated levels of the repressive H3K27me3 histone modification.

Novel therapeutic advances designed to boost adult neurogenesis may serve to aid the recovery from conditions such as stroke, and the findings from this exciting new study suggest that lncRNA‐based therapeutic strategies, especially those involving H19, may serve this purpose.

For more on how lncRNAs control the neurogenesis of NSCs and mediate recovery from stroke, stay tuned to the Stem Cells Portal!

References

  1. Jin K, Minami M, Lan JQ, et al., Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proceedings of the National Academy of Sciences 2001;98:4710.
  2. Jin K, Wang X, Xie L, et al., Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences 2006;103:13198.
  3. Liu XS, Chopp M, Zhang RL, et al., MicroRNA Profiling in Subventricular Zone after Stroke: MiR-124a Regulates Proliferation of Neural Progenitor Cells through Notch Signaling Pathway. PLOS ONE 2011;6:e23461.
  4. Liu XS, Fan BY, Pan WL, et al., Identification of miRNomes associated with adult neurogenesis after stroke using Argonaute 2-based RNA sequencing. RNA Biology 2017;14:488-499.
  5. Fan B, Pan W, Wang X, et al., Long noncoding RNA mediates stroke-induced neurogenesis. STEM CELLS 2020;38:973-985.
  6. Ramos Alexander D, Andersen Rebecca E, Liu Siyuan J, et al., The Long Noncoding RNA Pnky Regulates Neuronal Differentiation of Embryonic and Postnatal Neural Stem Cells. Cell Stem Cell 2015;16:439-447.
  7. Ng S-Y, Bogu Gireesh K, Soh Boon S, et al., The Long Noncoding RNA RMST Interacts with SOX2 to Regulate Neurogenesis. Molecular Cell 2013;51:349-359.
  8. Wang J, Zhao H, Fan Z, et al., Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1–Dependent M1 Microglial Polarization. Stroke 2017;48:2211-2221.