Researchers regenerate inner ear hair cells via the Notch pathway to restore hearing.


Sensory hair cell loss is the major cause of hearing loss and balance disorders. The postnatal mammalian inner ear harbors progenitor cells which have the potential for hair cell regeneration and hearing recovery, but the mechanisms that control their proliferation and hair cell regeneration are yet to be determined. Now scientists from the Harvard Medical School and Fudan University have shown that blocking the Notch pathway, known to control the elaborate hair cell distribution in the inner ear, plays an essential role that determines cochlear progenitor cell proliferation capacity. The research is published in Proceedings of the National Academy of Sciences.

A high level of Notch activity prevents progenitor cell division and hair cell regeneration in the postnatal inner ear.  The team state that they learned something new about this mechanism. It is known that inhibition of Notch activity can convert inner ear supporting cells to hair cells. In this paper, the researchers have shown that Notch inhibition also promotes cell division.  Under the condition, the inner ear progenitor cells re-enter cell division to regenerate hair cells in postnatal cochlea.

This study therefore provides a new route to block Notch activity to increase progenitor cell population by cell division, and to regenerate new hair cells. The researchers state that the work could have potential in leading to developing new strategies to achieve hair cell regeneration for hearing restoration.

The researchers show that Notch inhibition initiates proliferation of supporting cells that give rise to new hair cells in postnatal mouse cochlea in vivo and in vitro. Through lineage tracing, they identified that a majority of the proliferating supporting cells and cell division-generated hair cells induced by Notch inhibition are originated from the Wnt-responsive leucine-rich repeat-containing G protein coupled receptor 5 (Lgr5+) progenitor cells. They demonstrated that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5+ progenitor cells to mitotically generate new hair cells.

The team summise that the study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.

Source:  Massachusetts Eye and Ear/Harvard Medical School Teaching Hospital

Notch inhibition initiates SC proliferation and mitotic HC generation in vitro. (A) Representative low-magnification image of neonatal WT cochlea cultured for 3 d. (B and C) With EdU labeling, proliferation was detected in Sox2+ SCs and Myo7a+ HCs only after DAPT (C) but not in DMSO (B) treatment groups, respectively.  (D and E) Compared with the apex region, a lower number of BrdU+/Sox2+ SCs and BrdU+/Myo7a+ HCs were detected in the midapex and midbase regions after DAPT treatment.  Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway.  Li et al 2014.

Notch inhibition initiates SC proliferation and mitotic HC generation in vitro. (A) Representative low-magnification image of neonatal WT cochlea cultured for 3 d. (B and C) With EdU labeling, proliferation was detected in Sox2+ SCs and Myo7a+ HCs only after DAPT (C) but not in DMSO (B) treatment groups, respectively.
(D and E) Compared with the apex region, a lower number of BrdU+/Sox2+ SCs and BrdU+/Myo7a+ HCs were detected in the midapex and midbase regions after DAPT treatment. Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Li et al 2014.

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