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Novel Cell Conversion Approach to Neural Regeneration and Hearing Loss Reversal

Review of “Lin28 reprograms inner ear glia to a neuronal fate” from STEM CELLS by Stuart P. Atkinson

Researchers led by Albert S.B. Edge (Harvard Medical School, Boston, Massachusetts, USA) recently established that proteolipid protein 1 (Plp1)-expressing glial cells act as progenitors within the inner ear in that they spontaneously differentiate into neurons that grow neurites and form synapses [1-4]. Therefore, the team hypothesized that the in vivo induced conversion of Plp1-expressing glia into neurons might represent an exciting cell replacement approach in patients suffering from hearing loss due to the deficiency or functional impairment of auditory neurons.

Given a wide range of studies linking the expression of the Lin28 RNA binding protein with neural differentiation and the fact that Lin28 expression occurs during early cochlear development [5, 6], researchers from the Edge group recently explored the forced expression of Lin28 in Plp1-expressing glial cells as a means to induce the desired conversion process. Reporting in their new STEM CELLS article [7], Kempfle et al. now establish Lin28-mediated conversion of inner-ear glia into neurons as an exciting new approach to the replacement of lost/damaged auditory nerves and the reversal of hearing loss.

The authors established that Lin28 expression promoted the proliferation of auditory glial cells grown as neurospheres in vitro and prompted their reprogramming into neurons by activating proneural basic helix-loop-helix transcription factors through inhibition of the Let-7 microRNA. Subsequently, the team examined the effect of the transient overexpression of Lin28 in glial cells in vivo following selective damage to auditory neurons in an adult mouse model of auditory neuropathy. Encouragingly, analysis after one month established that the short-term expression of Lin28 prompted the appearance of neural stem cell markers in glial cells and the reprogramming of glia into neurons. Mechanistically, Lin28 overexpression stimulated the proliferation of inner ear glia and reprogramming to neurons through the Sox2 and Hmga2 stem cell regulatory genes, a finding that provides a targetable pathway that could enhance regeneration in the inner ear following the damage to auditory neurons.

In summary, the authors provide evidence that inner ear glia represents an endogenous source of reprogrammable cells for regenerative therapies and that the modulation of the Sox2‐Lin28/Let‐7 axis may represent an exciting new means to induce neuronal regeneration within the auditory system.

For more on in vivo reprogramming efforts and all the novel therapeutic approaches to hearing loss, stay tuned to the Stem Cells Portal!

References

  1. Martinez-Monedero R, Yi E, Oshima K, et al., Differentiation of Inner Ear Stem Cells to Functional Sensory Neurons. Developmental Neurobiology 2008;68:669-684.
  2. McLean WJ, McLean DT, Eatock RA, et al., Distinct Capacity for Differentiation to Inner Ear Cell Types by Progenitor Cells of the Cochlea and Vestibular Organs. Development 2016;143:4381.
  3. McLean WJ, Yin X, Lu L, et al., Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Reports 2017;18:1917-1929.
  4. Diensthuber M, Zecha V, Wagenblast J, et al., Spiral Ganglion Stem Cells can be Propagated and Differentiated into Neurons and Glia. BioResearch Open Access 2014;3:88-97.
  5. Sajan SA, Warchol ME, and Lovett M, Toward a Systems Biology of Mouse Inner Ear Organogenesis: Gene Expression Pathways, Patterns and Network Analysis. Genetics 2007;177:631.
  6. Doetzlhofer A and Avraham KB, Insights into Inner Ear-specific Gene Regulation: Epigenetics and Non-coding RNAs in Inner Ear Development and Regeneration. Seminars in Cell & Developmental Biology 2017;65:69-79.
  7. Kempfle JS, Luu N-NC, Petrillo M, et al., Lin28 reprograms inner ear glia to a neuronal fate. STEM CELLS 2020;38:890-903.