Molecular characterization and prospective isolation of human fetal cochlear hair cell progenitors

Roccio, Marta; Perny, Michael; Ealy, Megan; Widmer, HR; Heller, Stefan; Senn, Pascal

doi:10.1038/s41467-018-06334-7

Cited by 61 publications

(85 citation statements)

References 68 publications

(81 reference statements)

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“…The advantage of using fetal sources seems to be the fact that higher numbers of progenitor cells exist, which leads to a much more robust generation of differentiated inner ear cells. Our own recent studies corroborate the fact that cochlear hair cell‐like cells and neuron‐like cells can be robustly generated from human fetal sources (Roccio et al, ).…”

Section: Discussionsupporting

confidence: 84%

Progenitor Cells from the Adult Human Inner Ear

Senn

Mina

Volkenstein

et al. 2019

The Anatomical Record

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Loss of inner ear hair cells leads to incurable balance and hearing disorders because these sensory cells do not effectively regenerate in humans. A potential starting point for therapy would be the stimulation of quiescent progenitor cells within the damaged inner ear. Inner ear progenitor/stem cells, which have been described in rodent inner ears, would be principal candidates for such an approach. Despite the identification of progenitor cell populations in the human fetal cochlea and in the adult human spiral ganglion, no proliferative cell populations with the capacity to generate hair cells have been reported in vestibular and cochlear tissues of adult humans. The present study aimed at filling this gap by isolating colony‐forming progenitor cells from surgery‐ and autopsy‐derived adult human temporal bones in order to generate inner ear cell types in vitro. Sphere‐forming and mitogen‐responding progenitor cells were isolated from vestibular and cochlear tissues. Clonal spheres grown from adult human utricle and cochlear duct were propagated for a limited number of generations. When differentiated in absence of mitogens, the utricle‐derived spheres robustly gave rise to hair cell‐like cells, as well as to cells expressing supporting cell‐, neuron‐, and glial markers, indicating that the adult human utricle harbors multipotent progenitor cells. Spheres derived from the adult human cochlear duct did not give rise to hair cell‐like or neuronal cell types, which is an indication that human cochlear cells have limited proliferative potential but lack the ability to differentiate into major inner ear cell types. Anat Rec, 303:461–470, 2020. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

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Section: Discussionsupporting

confidence: 84%

Progenitor Cells from the Adult Human Inner Ear

Senn

Mina

Volkenstein

et al. 2019

The Anatomical Record

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“…Other studies have evidenced that GATA3 expression is crucial towards the development of the otic vesicle and the semicircular canals (Moriguchi et al 2018) while activating FGF10 in the early inner ear (Economou et al 2013;Pauley et al 2003). In the developing human fetus, the expression of GATA3 presents in the cochlear duct and the spiral ganglion between gestational weeks 8 and 12 (Roccio et al 2018).…”

Section: Introductionmentioning

confidence: 96%

“…The other similar G protein coupled receptor LGR6, a WNT signaling mediator is, however, able to generate more hair cells than LGR5+ progenitors (Zhang et al 2018). In situ hybridization probes specific for LGR5 have been able to localize LGR5 mRNA in the prosensory domain of the developing human cochlea at gestational week 9 (Roccio et al 2018).…”

Section: Introductionmentioning

confidence: 99%

“…This sets the stage for the cessation of the prosensory domain formation. Immediately before this, the cell cycle exit progression of spiral ganglion neurons from base to apex of the cochlear occurs (between gestational weeks 8 and 12) (Fritzsch et al 2019;Matei et al 2005;Roccio et al 2018). Scant information currently exists on the expression profile of the SOX2 transcription factor in the developing human vestibule.…”

Section: Introductionmentioning

confidence: 99%

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Early appearance of key transcription factors influence the spatiotemporal development of the human inner ear

et al. 2019

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Expression patterns of transcription factors leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), transforming growth factor-β-activated kinase-1 (TAK1), SRY (sex-determining region Y)-box 2 (SOX2), and GATA binding protein 3 (GATA3) in the developing human fetal inner ear were studied between the gestation weeks 9 and 12. Further development of cochlear apex between gestational weeks 11 and 16 (GW11 and GW16) was examined using transmission electron microscopy.LGR5 was evident in the apical poles of the sensory epithelium of the cochlear duct and the vestibular end organs at GW11. Immunostaining was limited to hair cells of the organ of Corti by GW12. TAK1 was immune positive in inner hair cells of the organ of Corti by GW12 and colocalized with p75 neurotrophic receptor expression. Expression for SOX2 was confined primarily to the supporting cells of utricle at the earliest stage examined at GW9. Intense expression for GATA3 was presented in the cochlear sensory epithelium and spiral ganglia at GW9. Expression of GATA3 was present along the midline of both the utricle and saccule in the zone corresponding to the striolar reversal zone where the hair cell phenotype switches from type I to type II. The spatiotemporal gradient of the development of the organ of Corti was also evident with the apex of the cochlea forming by GW16. It seems that highly specific staining patterns of several transcriptions factors are critical in guiding the genesis of the inner ear over development. Our findings suggest that the spatiotemporal gradient in cochlear development extends at least until gestational week 16.

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“…Although progress has been made in transcriptionally mapping the distinct cells of the cochlea (Burns et al, 2015; Durruthy-Durruthy et al, 2014; Ealy et al, 2016; Waldhaus et al, 2015), we do not have a global and systematic answer to the question of how many distinct cell types exist within the cochlea, at what point during development they are specified, or what distinct transcriptional programs they express (Basch et al, 2016). Furthermore, there have been no previously published single cell datasets on human cochleas, and is only limited bulk transcriptional information reported (Roccio et al, 2018; Schrauwen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Development of the Mouse and Human Cochlea at Single Cell Resolution

Frumm

Park

et al. 2019

Preprint

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Summary Hearing loss is a common and disabling condition, yet our understanding of the physiologic workings of the inner ear has been limited by longstanding difficulty characterizing the function and characteristics of the many diverse, fragile, and rare cell types in the cochlea. Using single-cell RNA-sequencing and a novel clustering algorithm, CellFindR, we created a developmental map of the mouse and human cochlea, identifying multiple previously undescribed cell types, progenitor populations, and predicted lineage relationships. We additionally associated the expression of known hearing loss genes to the cell types and developmental timepoints in which they are expressed. This work will serve as a resource for understanding the molecular basis of hearing and designing therapeutic approaches for hearing restoration.

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Molecular characterization and prospective isolation of human fetal cochlear hair cell progenitors

Cited by 61 publications

References 68 publications

Progenitor Cells from the Adult Human Inner Ear

Progenitor Cells from the Adult Human Inner Ear

Early appearance of key transcription factors influence the spatiotemporal development of the human inner ear

Development of the Mouse and Human Cochlea at Single Cell Resolution

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