Abstract
BackgroundHearing loss affects 25% of the population at ages 60–69 years. Loss of the hair cells of the inner ear commonly underlies deafness and once lost this cell type cannot spontaneously regenerate in higher vertebrates. As a result, there is a need for the development of regenerative strategies to replace hair cells once lost. Stem cell-based therapies are one such strategy and offer promise for cell replacement in a variety of tissues. A number of investigators have previously demonstrated successful implantation, and certain level of regeneration of hair and supporting cells in both avian and mammalian models using rodent pluripotent stem cells. However, the ability of human stem cells to engraft and generate differentiated cell types in the inner ear is not well understood.MethodsWe differentiate human pluripotent stem cells to the pre-placodal stage in vitro then transplant them into the mouse cochlea after selective and complete lesioning of the endogenous population of hair cells.ResultsWe demonstrate that hair cell ablation prior to transplantation leads to increased engraftment in the auditory sensory epithelium, the organ of Corti, as well as differentiation of transplanted cells into hair and supporting cell immunophenotypes.ConclusionWe have demonstrated the feasibility of human stem cell engraftment into an ablated mouse organ of Corti.Graphical abstract
Highlights
Hearing loss affects 25% of the population at ages 60–69 years
Pluripotency markers were downregulated at differentiation, pre-placodal ectoderm (PPE) markers were upregulated with differentiation, and otic placode (OP) markers were partially upregulated (Fig. 1E)
LT2e cells were differentiated using the same method as WA09 human embryonic stem cells (hESC) and had similar gene expression patterns to WA09 cells (Additional Figure 1)
Summary
Loss of the hair cells of the inner ear commonly underlies deafness and once lost this cell type cannot spontaneously regenerate in higher vertebrates. A number of investigators have previously demonstrated successful implantation, and certain level of regeneration of hair and supporting cells in both avian and mammalian models using rodent pluripotent stem cells. The ability of human stem cells to engraft and generate differentiated cell types in the inner ear is not well understood. Hearing loss is most commonly caused by inner ear cochlear hair cell (HC) death, and the resulting hearing deficits have a profound, negative impact on the daily life of affected people. Other xenograft models combining an avian recipient of mammalian stem cells showed successful engraftment and differentiation of mouse stem cell-derived progenitor cells into the nascent chick auditory sensory epithelium [9, 10]. We focus our investigations on transplanting stem cells at an early otic fate, and we differentiated human embryonic stem cells (hESC) to pre-placodal ectoderm (PPE) using previously reported methods [17]
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