Differentiation of inner ear cell types from human-induced pluripotent stem cells for the therapeutic application in sensorineural hearing loss

Abstract

Abstract The auditory system is one of the most delicate and complex sensory systems in the human body. Any small defect, damage, or cell death in the inner ear results in different levels of hearing loss. Hearing loss is the most common sensory loss of the human body. In the auditory system, the sensory epithelium, lateral wall, and auditory nerves constitute the human hearing. In the sensory epithelium, the outer hair cells (OHCs), inner hair cells (IHCs), and supporting cells are the major functional cells. OHCs and IHCs in different regions of the cochlea are responsible for different frequencies of sounds, apex for low frequencies and basal region for high frequencies. The specificity and sensitivity of OHCs and IHCs in the apex, middle, and base of cochlea to different frequencies of sound or voice depend on the fine differences in the length of the stereociliary hair bundles, number of stereocilia, number of ion channels, conduction transduction, and number and size of synaptic ribbons. Many etiological factors are known to cause damage or loss of HCs, such as loud noise, aging, genetic mutations, ototoxicity, infections, or unknown illnesses. Therefore, HCs are a major therapeutic target for sensorineural hearing loss. Additionally, the sulcus cells and fibrocytes in the cochlear lateral wall are important in the regulation of ion transport in the cochlea, which is crucial for human hearing. Moreover, the spiral ganglion neurons (SGNs) in the auditory nerve play an important role in receiving the ribbon synapses from the HCs. Degeneration of HCs and SGNs can result in age-related hearing loss. In the past 2\xa0decades, adult stem cells, such as the mesenchymal stem cells (MSCs) derived from the bone marrow, umbilical cord, and cord blood have been demonstrated to have the capacity of tissue repair and remodeling. However, the regeneration capacity of adult MSCs in differentiating into functional cells is still controversial. As the groundbreaking study by Yamanaka and colleagues that reported the generation of induced pluripotent stem cells (iPSCs) with differentiation capacity toward most cell types in the three germ layers, regenerative medicine is expected to become the core of future medicine. In this chapter, we first introduce the human auditory system, including the principal cell types and cellular functions in the inner ear. Further, we discuss how HCs, outer sulcus cells, and SGNs can be differentiated from human iPSCs, through the stages of otic progenitor cells and neural progenitor cells, respectively. In summary, the iPSC technology is bound to impact human health significantly. We speculate that a combination of iPSC and CRISPR/Cas9 gene editing technology will pave the way for rapid advances in regenerative medicine in the future, and for the treatment of hearing loss.