Birds can turn the supporting cells in the cochlea into sensory hair cells, allowing them to retain their hearing. In mammals, this capacity appears only in the early postnatal period. Understanding how to reprogram adult mammalian supporting cells into hair cells could lead to regenerative therapies for hearing loss for humans.
The mouse is the standard and most common model for studying hearing—and hair cell regeneration—in mammals. But the mouse cochlea’s tiny size and location, in addition to its small number of hair cells (approximately 3,000), make studying the mouse cochlea difficult. To overcome this challenge, researchers have begun using organoids, miniature 3D organ-like structures that are grown in the lab.
Organoids are created by allowing specialized cells to grow and differentiate in a way that resembles the development of an actual organ. They allow scientists to model development and differentiation, and they can be used to identify the small molecules and genes that modulate these processes.
Transcription factors are proteins that regulate gene expression by turning genes "on" or "off." This figure maps out how a network of these factors drives the transdifferentiation of progenitor cells into hair cells in the cochlea. The size of each transcription factor represents the strength of its influence, or outdegree, on other factors in the network. Credit: Kalra et al./Cell Reports
Hearing Restoration Project members Ronna Hertzano, M.D., Ph.D., Seth Ament, Ph.D., and Albert Edge, Ph.D., and team used a protocol they developed and previously detailed to generate cochlear organoids from mouse Lgr5+ progenitor cells.
This well-demonstrated process differentiates the mouse neonatal cochlear progenitor cells into 3D organoids that preserve developmental pathways. In addition, it can generate large numbers of hair cells with intact stereociliary bundles, mechanotransduction channel activity, and molecular markers of native cells, including markers for both inner and outer hair cells.
In this most recent work, the team performed a comprehensive molecular characterization of these organoids at multiple time points in their differentiation, with results published in Cell Reports in November 2023.
Transcriptional signatures of maturing hair cells were apparent after 10 days of organoid differentiation. The team confirmed that the organoids mimic nearly all supporting cell and hair cell subtypes of the in vivo cochlea (hearing organ) as well as the utricle (balance organ).
The group studied how gene activity and chromatin structure (which controls access to DNA) change as supporting cells in the inner ear turn into hair cells. The data revealed regulatory networks of genes that control hair cell formation. The team confirmed known hair cell development regulators—Atoh1, Pou4f3, and Gfi1—and their analysis also predicted new transcription factors involved (proteins that control gene activity): Tcf4 and Ddit3.
These details gleaned from this regenerative process in the mouse organoid provides insights into how mammalian supporting cells could be reprogrammed into hair cells.
This is adapted from the paper in Cell Reports, whose coauthors also include 2019 Emerging Research Grants scientist Dunia Abdul-Aziz, M.D., and HRP bioinformatician Mahashweta Basu, Ph.D.
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