The ear a complex sense organ. Its shape is intimately linked with its proper function, and its anatomy is set up during embryo development. Any errors result in hearing or balance defects at birth with life-long impact on many aspects of daily life. Our limited understanding of human ear development hampers the discovery of genetic causes, limiting treatment development. Our 3D ear organoids from human iPSCs recapitulate some aspects of ear formation but are not perfect. The ear forms from a simple ear vesicle (EV), which then divides into compartments later generating different parts of the ear. If this subdivision goes awry, the ear is malformed. Here, we will combine ear and stem cell biology with state-of-the-art bioengineering tools to control in space and time the signals that regulate subdivision of EVs. We aim to establish a better model for the human ear and its development to enable investigating the molecular mechanisms underlying congenital ear disorders.
The student will…
i) Characterise subdivision of and signalling in EVs generated by current protocols by mining sc-RNAseq data and by assessing gene expression using immunocytochemistry and in situ hybridisation. Organoids will be imaged by light sheet microscopy and data analysed by 3D reconstruction. (Y1)
ii) Develop our nanoneedle platform for targeted delivery of nucleic acids to control the expression of key morphogens in space and time across inner ear organoids. In vivo, the EV is exposed to graded signals including the shh, BMP, RA and Wnt morphogens, which impose axial identity to the vesicle. (Y1/2).
iii) Investigate changes in EV subdivision after signal exposure using gene expression and spatial transcriptomics. (Y3/4)
This interdisciplinary project lies at the interface of developmental biology and bioengineering. Training in stem cell biology, gene expression, imaging, biomaterials design, gene delivery, and spatial transcriptomics will be provided.
