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miRNA Regulation of NSC Self-renewal and Differentiation

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Review of “MicroRNA-145 Regulates Neural Stem Cell Differentiation through the Sox2–Lin28 let-7 Signaling Pathway” from Stem Cells by Stuart P. Atkinson

A deeper understanding of the molecular mechanisms controlling neural stem cell (NSC) self-renewal and differentiation into neural and glial cells [1, 2] may help us to construct better therapies aimed at regenerating regions affected by injury, pathological conditions, or aging.

This idea led researchers from the laboratories of Susana Solá and Cecília Rodrigues (Universidade de Lisboa, Portugal) to study what influence the miR145 microRNA had on NSCs derived from mouse fetal forebrain. Why miR145? The inspiration for this line of study came from previous studies showing that miR145 expression induced differentiation of human ESCs [3] and that miR145 downregulation occurred in glial tumors [4, 5]. Together, these findings suggested that miR145 could play an important role in neuronal differentiation.

The labs’ new study, published in Stem Cells, now shows that miR145 does have an influence on the neuronal differentiation of NSCs and functions through the modulation of the Sox2–Lin28/let-7 pathway [6]. Could the description of this new regulatory mechanism allow us to construct strategies to modulate neurogenesis in the damaged brain?

So what did they initially find?

  • Increased miR145 expression coincided with the early stages of NSC differentiation 
  • Downregulation of miR145 (using an anti-miR) reduced neural marker expression, neurite number and outgrowth, but did not affect NSC markers

How does miR145 function? 

  • NSC differentiation also coincided with a decrease in Sox2 and Lin28 expression and an increase in let-7a and let-7b miRNA expression
    • miR145 targets Sox2 in ESCs [3]
    • Sox2-mediated neurogenesis regulation involves Lin28 [7], a post-transcriptional inhibitor of let-7 miRNA biogenesis
  • anti-miR treatment increased Sox2 and Lin28 levels and decreased let-7a and let-7b miRNA
  • Further experiments suggested that miR145 targeted regions in the 3′ untranslated regions of both Sox2 and Lin28, and so directly target their downregulation during NSC differentiation

This detailed study picks apart the precise mechanics of miR145 function through the Sox2–Lin28/let-7 network in NSCs, and may allow us to enhance NSC self-renewal or promote differentiation in vitro in order to create new effective treatment modalities. Now, we need to couple this to strategies which can increase survival, maturation, migration, and functional integration of NSCs and NSC derivatives to enhance stem cell therapy for human neurological disorders.

References

  1. Gage FH Mammalian neural stem cells. Science 2000;287:1433-1438.
  2. Conti L and Cattaneo E Neural stem cell systems: physiological players or in vitro entities? Nat Rev Neurosci 2010;11:176-187.
  3. Xu N, Papagiannakopoulos T, Pan G, et al. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 2009;137:647-658.
  4. Lee HK, Bier A, Cazacu S, et al. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor. PLoS One 2013;8:e54652.
  5. Lee HK, Finniss S, Cazacu S, et al. Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget 2013;4:346-361.
  6. Morgado AL, Rodrigues CM, and Sola S MicroRNA-145 Regulates Neural Stem Cell Differentiation Through the Sox2-Lin28/let-7 Signaling Pathway. Stem Cells 2016;34:1386-1395..Cimadamore F, Amador-Arjona A, Chen C, et al. SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors. Proc Natl Acad Sci U S A 2013;110:E3017-3026.