Lin28 reprograms inner ear glia to a neuronal fate.
Stem Cells. 2020 Apr 03;:
Authors: Kempfle JS, Luu NC, Petrillo M, Al-Asad R, Zhang A, Edge ASB
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 by selectively damaging auditory neurons with ouabain. After neural damage was confirmed by the auditory brainstem response, we briefly upregulated Lin28 in Plp1-expressing inner ear glial cells. One month later, we analyzed the cochlea for neural marker expression by quantitative RT-PCR and immunohistochemistry. We found that transient Lin28 overexpression in Plp1-expressing glial cells induced expression of neural stem cell markers and subsequent conversion into neurons. This suggests the potential for inner ear glia to be converted into neurons as a regeneration therapy for neural replacement in auditory neuropathy. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: Loss or damage of auditory neurons is associated with sensorineural hearing loss and deafness. To date, no cure is available and amplification, as well as cochlear implants, rely on surviving neurons to convey the auditory signal to the brain. Regeneration strategies focusing on endogenous cell therapy may offer a future treatment option for replacement of lost neurons to restore the auditory circuit. We show here that in a transgenic mouse model, Plp1-positive glial cells of the inner ear have a capacity for regeneration and differentiate into neurons after transient activation of neural stem cell regulator Lin28 in vitro and in vivo. We present evidence that Lin28 acts through stem cell regulatory genes, Sox2 and Hmga2, to stimulate proliferation and reprogramming of inner ear glia to neurons raising the possibility of a new avenue for regeneration that could replace dying neurons in auditory neuropathy.
PMID: 32246510 [PubMed – as supplied by publisher]