Ranya Dano
Pronouns: she/her
Research Mentor(s): Robert Duncan
Research Mentor School/College/Department: Kresge Hearing Research Institute / Medicine
Program: UROPF
Session: Session 5 (2:40pm – 3:30pm)
Authors: R. Keith Duncan, Ranya Dano, Liqian Liu, Andrew Wylie
Abstract
Hearing loss and balance disorders are highly prevalent and often involve inner ear damage. Investigations into the mechanisms, prevention, and treatment of disease are hindered by the fragility of the inner ear, poor access, and scarcity of material. Our lab recently developed an in vitro method for generating inner ear organoids from pluripotent stem cells, allowing us to produce inner ear cell types for downstream applications such as regenerative medicine and disease modeling. However, organoid production is inefficient, highly heterogeneous, and limited to in-cell fates. One of the earliest signals in inner ear maturation in vivo is retinoic acid (RA). In the early phase, RA establishes an anterior-posterior gradient that divides the otic vesicle into sensory and non-sensory domains. In the late phase, RA further specifies sensory cell subtypes in each organ; notably, high RA specifies the peripheral boundaries of vestibular organs while low RA specifies the central domains. We developed methods to modulate RA signaling in vivo during the early phase of otic vesicle formation and the late phase of organoid formation. In the early phase, increasing RA dose resulted in increased expression of non-sensory markers (Lmx1a) and decreased expression of sensory markers (Sox2 and Lfng). We also observed a non-monotonic effect (i.e. Goldilocks phenomenon) on the efficiency of organoid formation, suggesting that a mixture of sensory and non-sensory domains is required to form the largest cystic organoids. Experiments with RA in late-phase cultures are ongoing. In these experiments, we expect RA excess to produce sensory cells with markers for the peripheral zones of vestibular organs (Spp1) and RA deficiency to produce markers for the central zones (Ocm). If our hypotheses are supported, we can use this culture system to further investigate RA regulation of inner ear development in a highly controlled in vitro system.
