A single-nucleus transcriptomic atlas of human inner ear development

Nature Neuroscience

Abstract

Hearing and balance rely on coordinated activity of multiple inner ear cell types, yet the mechanisms governing their development and specification in humans remain unclear. Consequently, this limits our understanding of how disease genes affect cell type formation and function, limiting the development of targeted treatments, including gene therapies. Here we present the Human Inner Ear Development snRNA-seq Atlas (HIEDRA), a single-nucleus transcriptomic atlas of the human inner ear spanning the first and second trimesters. HIEDRA maps sensory and nonsensory epithelia, neurons and mesenchyme-associated populations, including undercharacterized secretory cells required for ion homeostasis. We identify selective vulnerability in sensory and secretory lineages to disease-associated genes, infer regulatory networks and show that Hedgehog signaling suppression is required for secretory cell specification. We validate this mechanism in human inner ear organoids, expanding the model to include all major cell types. Altogether, these findings provide insights into human inner ear cell type specification, improve in vitro models and establish HIEDRA as a resource for investigating human inner ear development.

Authors 11

1. Wouter H. van der Valk corresponding Aachen OtoBiology Leiden Department of Otorhinolaryngology and Head & Neck Surgery Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)

   Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine

   Affiliation as printed

   OtoBiology Leiden, Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands. w.h.van_der_valk@lumc.nl

   The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the Netherlands. w.h.van_der_valk@lumc.nl

2. Shantha D. Udayappan Aachen OtoBiology Leiden Department of Otorhinolaryngology and Head & Neck Surgery Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)

   Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine

   Affiliation as printed

   OtoBiology Leiden, Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands

   The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the Netherlands

3. Edward S. A. van Beelen Aachen OtoBiology Leiden Department of Otorhinolaryngology and Head & Neck Surgery

   Leiden University Medical Center

   Affiliation as printed

   OtoBiology Leiden, Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands

4. Jermaine Goveia
   Affiliation as printed

   Unicle Biomedical Data Science, Leuven, Belgium

5. Aleksandar Beatovic
   Affiliation as printed

   Unicle Biomedical Data Science, Leuven, Belgium

6. Matthieu Moisse
   Affiliation as printed

   Unicle Biomedical Data Science, Leuven, Belgium

7. Roberta Menafra Aachen Leiden Genome Technology Center Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

8. John C.M.J. de Groot Aachen OtoBiology Leiden Department of Otorhinolaryngology and Head & Neck Surgery Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)

   Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine

   Affiliation as printed

   OtoBiology Leiden, Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands

   The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the Netherlands

9. Karl R. Koehler

   Boston Children's Hospital · Harvard University

   Affiliation as printed

   Department of Otolaryngology, Department of Dermatology, Department of Plastic and Oral Surgery, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA

   Department of Otolaryngology-Head and Neck Surgery, Department of Dermatology, Harvard Medical School, Boston, MA, USA

10. Peter Paul G. van Benthem Aachen OtoBiology Leiden Department of Otorhinolaryngology and Head & Neck Surgery

    Leiden University Medical Center

    Affiliation as printed

    OtoBiology Leiden, Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands

11. Heiko Locher Aachen OtoBiology Leiden Department of Otorhinolaryngology and Head & Neck Surgery Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)

    Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine

    Affiliation as printed

    OtoBiology Leiden, Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands

    The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the Netherlands