Principal Research Fellow University of Melbourne, United States
Abstract: Normal inner ear development requires the sophisticated orchestration of specialised cell differentiation and integration, which ultimately gives rise to the exquisite organs of hearing and balance. We are only just beginning to understand the timeline and dynamic nature of this process in the developing human inner ear. Recent studies using single cell transcriptomics have improved our understanding of the various cellular phenotypes present in the mammalian inner ear. During human inner ear development, macrophages have been identified as early as gestational week 7 by expression of IBA1 and CD45 and clearly populate the adult cochlea. Yet, there is little known about the origin of cochlear macrophages, or their functional contributions to inner ear organogenesis.
Using a transcriptional approach, we have identified seven distinct macrophage subtypes present over a broad window of human inner ear development which spans foetal weeks 7.5, 9.2, 18, 18.4 and adult. We describe differential gene expression in each of these unique macrophage subtypes, including how each subtype is closely linked to a specific developmental age. These data support and extend upon existing histological studies in the human inner ear, reporting the presence of resident and non-resident macrophages in both the developing cochlea, and in adult cochleae following cochlear implantation. In addition, we report that human inner ear macrophages are seeded from multiple sources, supporting the conclusions from recent studies in mice indicating yolk sac and foetal liver origins. We discuss the possible functions of the unique macrophage phenotypes identified at different developmental ages, by analysing their ligand-receptor interactions with other key cell types present during inner ear development.
Together, these data highlight for the first time, the breadth of macrophage phenotypes present throughout human inner ear development and their possible multi-disciplinary contributions to normal inner ear organogenesis. A more comprehensive understanding of the functional roles of human inner ear macrophages will accelerate novel therapeutic strategies targeting both immune-, congenital and age-related hearing loss.
Funding Source: The University of Melbourne - University of Toronto Joint Collaborative Research Grant
