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Am J Transl Res. 2016 Feb 15;8(2):634-43. eCollection 2016.

DAPT mediates atoh1 expression to induce hair cell-like cells.

Author information

1
Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University Guangzhou 510080, Guangdong, P.R. China.
2
Department of Otolaryngology Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital Beijing, China.
3
Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University No. 139 Middle Renmin Road, Changsha 410011, Hunan, P.R. China.
4
Renji-MedX Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China; Med-X Research Institute, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China.

Abstract

Hearing loss is currently an incurable degenerative disease characterized by a paucity of hair cells (HCs), which cannot be spontaneously replaced in mammals. Recent technological advancements in gene therapy and local drug delivery have shed new light for hearing loss. Atoh1, also known as Math1, Hath1, and Cath1, is a proneural basic helix-loop-helix (bHLH) transcription factor that is essential for HC differentiation. At various stages in development, Atoh1 activity is sufficient to drive HC differentiation in the cochlea. Thus, Atoh1 related gene therapy is the most promising option for HC induction. DAPT, an inhibitor of Notch signaling, enhances the expression of Atoh1 indirectly, which in turn promotes the induction of a HC fate. Here, we show that DAPT cooperates with Atoh1 to synergistically promote HC fate in ependymal cells in vitro and promote hair cell regeneration in the cultured basilar membrane (BM) which mimics the microenvironment in vivo. Taken together, our findings demonstrated that DAPT is sufficient to induce HC-like cells via enhancing of the expression of Atoh1 to inhibit the progression of HC apoptosis and to induce new HC formation.

KEYWORDS:

DAPT; Hearing loss; atoh1; ependymal cells; hair cells

PMID:
27158355
PMCID:
PMC4846912

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