Directed differentiation and direct reprogramming: Applying stem cell technologies to hearing research

Abstract

Hearing loss is the most widely spread sensory disorder in our society. In the majority of cases, it is caused by the loss or malfunctioning of cells in the cochlea: the mechanosensory hair cells, which act as primary sound receptors, and the connecting auditory neurons of the spiral ganglion, which relay the signal to upper brain centers.In contrast to other vertebrates, where damage to the hearing organ can be repaired through the activity of resident cells, acting as tissue progenitors, in mammals, sensory cell damage or loss is irreversible. The understanding of gene and cellular functions, through analysis of different animal models, has helped to identify causes of disease and possible targets for hearing restoration. Translation of these findings to novel therapeutics is, however, hindered by the lack of cellular assays, based on human sensory cells, to evaluate the conservation of molecular pathways across species and the efficacy of novel therapeutic strategies. In the last decade, stem cell technologies enabled to generate human sensory cell types in vitro, providing novel tools to study human inner ear biology, model disease, and validate therapeutics. This review focuses specifically on two technologies: directed differentiation of pluripotent stem cells and direct reprogramming of somatic cell types to sensory hair cells and neurons. Recent development in the field are discussed as well as how these tools could be implemented to become routinely adopted experimental models for hearing research.

WNT Activation and TGFβ-Smad Inhibition Potentiate Stemness of Mammalian Auditory Neuroprogenitors for High-Throughput Generation of Functional Auditory Neurons In Vitro

“…Inner ear organoids, either derived from iPSC or from ES constitute, thus far, the most relevant alternative to animal experimentation [ 52 , 53 ]. In particular, recent advances in directed differentiation of human iPSC allowed the development of heterotypic cochlear organoids recapitulating the sensory hair cells and associated auditory neuron physiology [ 54 , 55 ].…”

Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors

“…While human fetal and adult (postmortem or surgically derived material) can be used for important validation studies, their limited accessibility in fact strongly hampers the use in routine or high throughput experimental settings (Chen et al, 2007;Roccio et al, 2018;Taylor et al, 2018). Generation of human cell types using stem cell technologies may provide alternative and scalable tools for in vitro testing of drug therapies (Koehler et al, 2017;Roccio, 2020). In conclusion, while the tested GSI reliably enhanced de novo hair cell formation in vitro in all the presented assays, a major future hurdle will be to generate advanced models that are representative of mature or aged tissues to study disease and regeneration in these settings prior to the translation to more complex in vivo models.…”

Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss

“…Moreover, these cells continued their differentiation towards a HC-like lineage following their integration into the sensory epithelia of otic vesicles in chicken embryos; an upregulation in the expression of MYO7A and the hair bundle protein espin (ESPN) was recorded. A series of studies has since attempted the differentiation of pluripotent stem cells (ESCs and iPSCs, of murine and human origins) to otic cell lineages; for detailed reviews on these studies, we refer the reader to some earlier publications [ 20 , 39 , 40 , 41 ]. Within the scope of this review, we address the work that has been carried out using hiPSCs ( Table 1 ), briefly mentioning some results obtained with ESCs.…”