In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Li, Xiang; Bi, Zhenghong; Sun, Yidi; Li, Chao; Li, Yixue; Li, Yong

doi:10.1096/fj.201902118r

Cited by 19 publications

(17 citation statements)

References 49 publications

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“…The genetic constructs were designed such that upon Cre-mediated recombination, Tdtomato and Ikzf2 would be translated, initially together from the same polycistronic mRNA, and subsequently cleaved by the 2A peptide ( Li et al, 2020a ); and once triggered, expression of Ikzf2 and Tdtomato would be permanent, enabling genetic fate-mapping analysis at single-cell resolution. Thus, this construct, when used in conjunction with a SC-specific Cre-driver, would readily allow us to distinguish potential new OHCs (Tdtomato+) derived from adult cochlear SCs (primarily PCs and DCs in this study) from endogenous OHCs (Tdtomato−).…”

Section: Resultsmentioning

confidence: 99%

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Sun

Luo

et al. 2021

eLife

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Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

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Section: Resultsmentioning

confidence: 99%

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Sun

Luo

et al. 2021

eLife

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“…Heterozygous and homozygous Rosa26-CAG-LSL-Ikzf2 mice were healthy and fertile, and did not display any apparent phenotypes. Upon Cre-mediated recombination, Tdtomato and Ikzf2 were initially translated together from the same polycistronic mRNA, and subsequently separated by the 2A peptide (Li et al, 2020b). Once triggered, the expression of Ikzf2 and Tdtomato was permanent, which enabled genetic fate-mapping analysis at single-cell resolution.…”

Section: Resultsmentioning

confidence: 99%

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Sun

Luo

et al. 2021

Preprint

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Mammalian cochlear outer hair cells (OHCs) are essential for hearing. OHC degeneration causes severe hearing impairment. Previous attempts of regenerating new OHCs from cochlear supporting cells (SCs) had yielded cells lacking Prestin, a key motor protein for OHC function. Thus, regeneration of Prestin+ OHCs remains a challenge for repairing OHC damage in vivo. Here, we reported that successful in vivo conversion of adult cochlear SCs into Prestin+ OHC-like cells could be achieved by simultaneous expression of Atoh1 and Ikzf2, two key transcriptional factors necessary for OHC development. New OHC-like cells exhibited upregulation of hundreds of OHC genes and downregulation of SC genes. Single cell transcriptomic analysis demonstrated that the differentiation status of these OHC-like cells was much more advanced than previously achieved. Thus, we have established an efficient approach to promote regeneration of Prestin+ OHCs and paved the way for repairing damaged cochlea in vivo via transdifferentiation of SCs.

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“…However, a direct comparison of glial subpopulations is lacking and the iNs did not appear to mature as SGNs. Importantly, two groups recently reported that iNs can be generated from Plp1 + glial cell by Ng1/Nd1 or Lin28 overexpression in vivo post-SGN injury, and that iNs expressed both pan-neuronal and SGN markers ( Kempfle et al, 2020 ; Li X. et al, 2020 ). However, the efficiency of neuronal conversion and neuronal maturity is still limited.…”

Section: Discussionmentioning

confidence: 99%

Cochlear Sox2+ Glial Cells Are Potent Progenitors for Spiral Ganglion Neuron Reprogramming Induced by Small Molecules

Chen

Huang

et al. 2021

Front. Cell Dev. Biol.

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In the mammalian cochlea, spiral ganglion neurons (SGNs) relay the acoustic information to the central auditory circuits. Degeneration of SGNs is a major cause of sensorineural hearing loss and severely affects the effectiveness of cochlear implant therapy. Cochlear glial cells are able to form spheres and differentiate into neurons in vitro. However, the identity of these progenitor cells is elusive, and it is unclear how to differentiate these cells toward functional SGNs. In this study, we found that Sox2+ subpopulation of cochlear glial cells preserves high potency of neuronal differentiation. Interestingly, Sox2 expression was downregulated during neuronal differentiation and Sox2 overexpression paradoxically inhibited neuronal differentiation. Our data suggest that Sox2+ glial cells are potent SGN progenitor cells, a phenotype independent of Sox2 expression. Furthermore, we identified a combination of small molecules that not only promoted neuronal differentiation of Sox2– glial cells, but also removed glial cell identity and promoted the maturation of the induced neurons (iNs) toward SGN fate. In summary, we identified Sox2+ glial subpopulation with high neuronal potency and small molecules inducing neuronal differentiation toward SGNs.

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In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Cited by 19 publications

References 49 publications

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Cochlear Sox2+ Glial Cells Are Potent Progenitors for Spiral Ganglion Neuron Reprogramming Induced by Small Molecules

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