Stepwise Induction of Inner Ear Hair Cells From Mouse Embryonic Fibroblasts via Mesenchymal- to-Epithelial Transition and Formation of Otic Epithelial Cells

• Main Authors: Qiong Yang, Haosong Shi, Yizhou Quan, Qianqian Chen, Wang Li, Li Wang, Yonghui Wang, Zhongzhong Ji, Shan-Kai Yin, Hai-Bo Shi, Huiming Xu, Wei-Qiang Gao
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-06-01
• Series: Frontiers in Cell and Developmental Biology
• Subjects: hair cell regeneration; mesenchymal-to-epithelial transition (MET); hearing loss; mouse embryonic fibroblasts; transdifferentiation
• Online Access: https://www.frontiersin.org/articles/10.3389/fcell.2021.672406/full

Although embryonic stem cells or induced pluripotent stem cells are able to differentiate into inner ear hair cells (HCs), they have drawbacks limiting their clinical application, including a potential risk of tumourigenicity. Direct reprogramming of fibroblasts to inner ear HCs could offer an alternative solution to this problem. Here, we present a stepwise guidance protocol to induce mouse embryonic fibroblasts to differentiate into inner ear HC-like cells (HCLs) via mesenchymal-to-epithelial transition and then acquisition of otic sensory epithelial cell traits by overexpression of three key transcription factors. These induced HCLs express multiple HC-specific proteins, display protrusions reminiscent of ciliary bundle structures, respond to voltage stimulation, form functional mechanotransduction channels, and exhibit a transcriptional profile of HC signature. Together, our work provides a new method to produce functional HCLs in vitro, which may have important implications for studies of HC development, drug discovery, and cell replacement therapy for hearing loss.