Pluripotent stem cell-derived cochlear cells: a challenge in constant progress

Abstract

Hearing loss is a common affection mainly resulting from irreversible loss of the sensory hair cells of the cochlea; therefore, developing therapies to replace missing hair cells is essential. Understanding the mechanisms that drive their formation will not only help to unravel the molecular basis of deafness, but also give a roadmap for recapitulating hair cells development from cultured pluripotent stem cells. In this review, we provide an overview of the molecular mechanisms involved in hair cell production from both human and mouse embryonic stem cells. We then provide insights how this knowledge has been applied to differentiate induced pluripotent stem cells into otic progenitors and hair cells. Finally, we discuss the current limitations for properly obtaining functional hair cell in a Petri dish, as well as the difficulties that have to be overcome prior to consider stem cell therapy as a potential treatment for hearing loss.

Keywords: Differentiation; Hair cells; Inner ear; Otic progenitors; Stem cells.

Fig. 1

Different steps of embryonic development from the blastocyst to the inner ear hair cells. Pluripotent inner cell mass of the blastocyst can generate the three germ layers: the endoderm, the mesoderm and the ectoderm. Transient BMP activation induces the differentiation of the ectoderm into the non-neural ectoderm (NNE), characterised by the expression of Tfap2a, Tfap2c, and Gata3. Combination of FGF activation, and Wnt and BMP inhibition leads to the formation of the preplacodal region (PPR) expressing Six 1, Eya1 and Eya4 transcription factors. The difference cranial sensory organs arise from this PPR. Its most posterior part, the otic and epibranchial placode domain (OEPD) further differentiates into the otic placode under the control of FGF and Wnt pathways. Some otic placode-derived progenitors will then differentiate into spiral ganglion neurons as other will proliferate in a region called the prosensory domain to give rise to the Sox2-positive prosensory progenitors. Through lateral inhibition of Notch signalling pathway, those progenitors will differentiate into hair cells and supporting cells

Fig. 2

Comparison of published protocols for hair cell-like cells differentiation of mESCs. BMP bone morphogenetic protein, EB embryoid bodies, EGF epidermal growth factor, FGF fibroblast growth factor, IGF-1 insulin-like growth factor-1, LIF leukemia inhibitory factor, mESCs mouse embryonic stem cells, NNE non neural ectoderm, PPR pre placodal region, TGF-β transforming growth factor-β

Fig. 3

Comparision of published protocols of human ES and iPS cell differentiation into hair cell-like cells. BMP bone morphogenetic protein, EB embryoid bodies, EGF epidermal growth factor, FGF fibroblast growth factor, hESCs human embryonic stem cells, hPSCs human induced pluripotent sten cells, IGF-1 insulin-like growth factor 2, LIF leukemia inhibitory factor, NNE non neural ectoderm, OEPD otic epibranchial placode domain, PPR pre placodal region, RA retinoic acid, TCF-β transforming growth factor-β