Reprogramming Glia Into Neurons in the Peripheral Auditory System as a Solution for Sensorineural Hearing Loss: Lessons From the Central Nervous System

Meas, Steven J.; Zhang, Chun Li; Dabdoub, Alain

doi:10.3389/fnmol.2018.00077

Cited by 15 publications

(12 citation statements)

References 141 publications

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“…In the adult inner ear in vivo, reactive gliosis after damage may create an environment more permissive for transdifferentiation and neural reprogramming, similar to the CNS, 28,29 but to date, the contribution of Plp1-positive cells to postnatal gliogenesis and neurogenesis remains unclear. 30,31 The RNA binding protein, Lin28, together with Sox2, Oct4, and NANOG, can reinduce pluripotency in murine cells 32,33 ; Lin28 promotes proliferation of neural precursors.…”

Section: Introductionmentioning

confidence: 99%

Lin28 reprograms inner ear glia to a neuronal fate

et al. 2020

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Sensorineural hearing loss is irreversible and can be caused by loss of auditory neurons. Regeneration of neural cells from endogenous cells may offer a future tool to restore the auditory circuit and to enhance the performance of implantable hearing devices. Neurons and glial cells in the peripheral nervous system are closely related and originate from a common progenitor. Prior work in our lab indicated that in the early postnatal mouse inner ear, proteolipid protein 1 (Plp1) expressing glial cells could act as progenitor cells for neurons in vitro. Here, we used a transgenic mouse model to transiently overexpress Lin28, a neural stem cell regulator, in Plp1-positive glial cells. Lin28 promoted proliferation and conversion of auditory glial cells into neurons in vitro. To study the effects of Lin28 on endogenous glial cells after loss of auditory neurons in vivo, we produced a model of auditory neuropathy

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Section: Introductionmentioning

confidence: 99%

Lin28 reprograms inner ear glia to a neuronal fate

et al. 2020

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“…Additionally, it can be caused by damage to the stria vascularis that contributes to cochlear blood supply and ionic balance, as well as genetic hearing loss. 3 , 4 , 5 …”

Section: Main Textmentioning

confidence: 99%

Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration

2019

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Hearing loss is one of the most prevalent sensory deficits worldwide and can result from the death of mechanosensory hair cells that transduce auditory signals in the cochlea. The mammalian cochlea lacks the capacity to regenerate these hair cells once damaged, and currently there are no biological therapies for hearing loss. Understanding the signaling pathways responsible for hair cell development can inform regenerative strategies and identify targets for treating hearing loss. The canonical Wnt and Notch pathways are critical for cochlear development; they converge on several key molecules, such as Atoh1, to regulate prosensory specification, proliferation, hair cell differentiation, and cellular organization. Much work has focused on Wnt and Notch modulation in the neonatal mouse cochlea, where they can promote hair cell regeneration. However, this regenerative response is limited in the adult cochlea and this might be attributed to age-dependent epigenetic modifications. Indeed, the epigenetic status at key gene loci undergoes dynamic changes during cochlear development, maturation, and aging. Therefore, strategies to improve regenerative success in the adult cochlea might require the modulation of Wnt, Notch, or other pathways, as well as targeted epigenetic modifications to alter the activity of key genes critical for supporting cell proliferation or transdifferentiation.

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“…It should be noted that the source of cells for reprogramming is important. Studies performed using astrocytes have discovered that reprogrammed cells developed into induced neurons that were similar to the endogenous neurons from the niche in which they were harvested (Meas et al, 2018 ). Hence, we are interested in using cells harvested from the spiral ganglion in order to induce neurons that are similar to endogenous PANs.…”

Section: Materials and Equipmentmentioning

confidence: 99%

“…Satellite glia and non-myelinating Schwann cells surround the cell bodies of PANs within the spiral ganglion. They play a similar role to glia within the central nervous system by supporting the functions of neuronal activity (Meas et al, 2018 ). For a complete review of PANs and their functions, please refer to Dabdoub et al ( 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…PANs do not have the capacity to regenerate, hence once they are lost their hearing function can never be restored. Therefore, it is important to develop a greater understanding of the biological parameters present within the spiral ganglion niche in a controlled environment to support research into regenerative strategies (Meas et al, 2018 ). Early studies on the inner ear relied on organotypic cultures of the chick embryonic otocyst, which offered researchers insights into the differentiation, growth, and development of inner ear cells in an avian model (Strangeways and Fell, 1926 ).…”

Section: Introductionmentioning

confidence: 99%

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In vitro Methods to Cultivate Spiral Ganglion Cells, and Purification of Cellular Subtypes for Induced Neuronal Reprogramming

et al. 2018

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Hearing loss can develop as a consequence of primary auditory neuron degeneration. These neurons are present within the spiral ganglion of the inner ear and co-exist with glial cells that assist in neuronal maintenance and function. There are limited interventions for individuals with hearing impairment, hence novel biological solutions must be explored. Regenerative strategies can benefit from in vitro methods to examine the long-term culture of purified cell populations. The culturing of neuronal, glial, and non-neuronal, non-glial cell types in both neonatal and adult mice is presented along with the whole-organ explant culture of the spiral ganglion. High yields of spiral ganglion glial and non-glial cells were cultured from both neonatal and adult mice. Dissociated spiral ganglion cells from Sox2-EGFP mice were sorted based on EGFP expression using fluorescence activated cell sorting. The EGFP+ fraction included purified glial populations, whereas the EGFP- fraction contained non-glial cells. Purified glial cells could be reprogrammed into induced neurons displaying neuronal markers and morphology at a higher efficiency than non-glial cells. Previous studies have only allowed for the short-term culturing of spiral ganglion cell populations and have placed emphasis on neonatal cells. There has also been a lack of methods able to cultivate pure cell populations. Here, the coupling of transgenic mouse lines, fluorescence activated cell sorting and advanced culture conditions allow cultivation and characterization of neuronal, glial and non-neuronal, non-glial cells from the spiral ganglion. These techniques are used to demonstrate that different spiral ganglion cell subtypes (glial vs. non-glial) display different competencies for direct neuronal reprogramming.

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Reprogramming Glia Into Neurons in the Peripheral Auditory System as a Solution for Sensorineural Hearing Loss: Lessons From the Central Nervous System

Cited by 15 publications

References 141 publications

Lin28 reprograms inner ear glia to a neuronal fate

Lin28 reprograms inner ear glia to a neuronal fate

Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration

In vitro Methods to Cultivate Spiral Ganglion Cells, and Purification of Cellular Subtypes for Induced Neuronal Reprogramming

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