Browsing by Author "van der Valk, Wouter H."

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    A single-cell level comparison of human inner ear organoids with the human cochlea and vestibular organs
    (Cell Press, 2023) van der Valk, Wouter H.; van Beelen, Edward S. A.; Steinhart, Matthew R.; Nist-Lund, Carl; Osorio, Daniel; de Groot, John C. M. J.; Sun, Liang; van Benthem, Peter Paul G.; Koehler, Karl R.; Locher, Heiko; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Inner ear disorders are among the most common congenital abnormalities; however, current tissue culture models lack the cell type diversity to study these disorders and normal otic development. Here, we demonstrate the robustness of human pluripotent stem cell-derived inner ear organoids (IEOs) and evaluate cell type heterogeneity by single-cell transcriptomics. To validate our findings, we construct a single-cell atlas of human fetal and adult inner ear tissue. Our study identifies various cell types in the IEOs including periotic mesenchyme, type I and type II vestibular hair cells, and developing vestibular and cochlear epithelium. Many genes linked to congenital inner ear dysfunction are confirmed to be expressed in these cell types. Additional cell-cell communication analysis within IEOs and fetal tissue highlights the role of endothelial cells on the developing sensory epithelium. These findings provide insights into this organoid model and its potential applications in studying inner ear development and disorders.
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    Building inner ears: recent advances and future challenges for in vitro organoid systems
    (Springer Nature, 2021-01) van der Valk, Wouter H.; Steinhart, Matthew R.; Zhang, Jingyuan; Koehler, Karl R.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    While inner ear disorders are common, our ability to intervene and recover their sensory function is limited. In vitro models of the inner ear, like the organoid system, could aid in identifying new regenerative drugs and gene therapies. Here, we provide a perspective on the status of in vitro inner ear models and guidance on how to improve their applicability in translational research. We highlight the generation of inner ear cell types from pluripotent stem cells as a particularly promising focus of research. Several exciting recent studies have shown how the developmental signaling cues of embryonic and fetal development can be mimicked to differentiate stem cells into "inner ear organoids" containing otic progenitor cells, hair cells, and neurons. However, current differentiation protocols and our knowledge of embryonic and fetal inner ear development in general, have a bias toward the sensory epithelia of the inner ear. We propose that a more holistic view is needed to better model the inner ear in vitro. Moving forward, attention should be made to the broader diversity of neuroglial and mesenchymal cell types of the inner ear, and how they interact in space or time during development. With improved control of epithelial, neuroglial, and mesenchymal cell fate specification, inner ear organoids would have the ability to truly recapitulate neurosensory function and dysfunction. We conclude by discussing how single-cell atlases of the developing inner ear and technical innovations will be critical tools to advance inner ear organoid platforms for future pre-clinical applications.
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    Mapping oto-pharyngeal development in a human inner ear organoid model
    (The Company of Biologists, 2023) Steinhart, Matthew R.; van der Valk, Wouter H.; Osorio, Daniel; Serdy, Sara A.; Zhang, Jingyuan; Nist-Lund, Carl; Kim, Jin; Moncada-Reid, Cynthia; Sun, Liang; Lee, Jiyoon; Koehler, Karl R.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Inner ear development requires the coordination of cell types from distinct epithelial, mesenchymal and neuronal lineages. Although we have learned much from animal models, many details about human inner ear development remain elusive. We recently developed an in vitro model of human inner ear organogenesis using pluripotent stem cells in a 3D culture, fostering the growth of a sensorineural circuit, including hair cells and neurons. Despite previously characterizing some cell types, many remain undefined. This study aimed to chart the in vitro development timeline of the inner ear organoid to understand the mechanisms at play. Using single-cell RNA sequencing at ten stages during the first 36 days of differentiation, we tracked the evolution from pluripotency to various ear cell types after exposure to specific signaling modulators. Our findings showcase gene expression that influences differentiation, identifying a plethora of ectodermal and mesenchymal cell types. We also discern aspects of the organoid model consistent with in vivo development, while highlighting potential discrepancies. Our study establishes the Inner Ear Organoid Developmental Atlas (IODA), offering deeper insights into human biology and improving inner ear tissue differentiation.