Main description:

This volume provides a detailed update on progress in the field of hair cell regeneration. This topic is of considerable interest to academicians, clinicians, and commercial entities, including students of auditory and vestibular neuroscience, audiologists, otologists, and industry, all of whom may have interest in hair cell regeneration as a potential future therapy for hearing and balance dysfunction. In 2008, Springer published a SHAR volume on this subject (Hair Cell Regeneration, Repair, and Protection, Editors Richard Salvi and Richard Fay). Since that time, there has been considerable advancement in this field.This book provides a historical perspective on the field, but the emphasis is on more "prospective" views of the various facets of regeneration research, in the hope that the volume will stimulate new projects and approaches, focusing on the limitations of current knowledge and describing promising strategies for future work. The book will include the following key features of hair cell regeneration:

* Cellular and molecular control hair cell regeneration in non-mammalian species (in particular zebrafish and chickens)

* Our current understanding of the capacity for hair cell replacement in mammals (rodents and humans).

* Signals controlling pro-regenerative behaviors in supporting cells, the hair cell progenitors.

* New techniques that have been applied to study the genetic and epigenetic regulation of hair cell regeneration in mammals and non-mammals.

* Contributions of stem cells toward building new tools to explore how hair cell regeneration is controlled and toward developing cells and tissue for therapeutic transplantation.

* Studies that have applied gene and drug therapy to promote regeneration in mammals.

Contents:

Chapter 1. Introduction and historical perspective

Jennifer Stone and Mark Warchol

This chapter will provide an overview of otic regeneration and introduce the concepts/topics that will be the focus of the following chapters. First, we will review the embryonic development of the ear and the lack (or paucity) of postnatal hair cell addition in mammals. This will be contrasted with studies demonstrating hair cell addition in the ears of elasmobranchs, fish and amphibians. We will then describe the basic phenomena of regeneration in the basilar papilla and vestibular organs of birds, and the limited regenerative potential of the vestibular organs of mammals. We will also give a brief overview of the fundamental mechanisms used by other neural tissues to execute sensory cell turnover and regeneration (taste, olfaction).

Chapter 2. Injury Signals in the Sensory Epithelium/Phagocytosis of Dying Hair Cells

Lisa Cunningham and to be identified co-writer

This chapter will discuss the morphological, cellular, and molecular changes that occur in the sensory epithelium (inner ear, lateral line) in response to hair cell death. It will include a review of how corpses of hair cells are removed from different sensory epithelia and correlate differences in these processes among sensory organs and species with differences in regenerative ability.

Chapter 3. Non-mammalian Hair Cell Regeneration: Cellular Mechanisms of Morphological and Functional Recovery

David Raible, Jennifer Stone, and to be identified co-writer

The current knowledge regarding the cellular and molecular mechanisms of non-mammalian hair cell regeneration in auditory, vestibular, and lateral line organs will be discussed, including mitotic and non-mitotic processes in supporting cells, supporting cell properties, lineages, and regional behaviors. The chapter will also address how maturation of regenerated hair cells and restoration of hearing, balance, and lateral line sensory epithelia, and it will touch on how supporting cell cytoskeletal structure may influence the regenerative ability of the ears of birds vs. mammals.

Chapter 4. Cytoskeletal and mechanical regulation of hair cell regeneration

Jeff Corwin and to be identified co-writer

Chapter 5. Mammalian Hair Cell Regeneration

Andrew Forge and Ruth Taylor

This chapter will be a comprehensive review of studies of regeneration in the mammalian inner ear; what is known in vestibular and auditory systems; what is known about cellular mechanisms by which new hair cells are (or are not) replaced; what changes that take place in mammalian supporting cells in response to hair cell injury. Comparative studies in neonatal versus mature mammalian sensory organs will be highlighted.

Chapter 6. Specification and Plasticity of Hair Cell Progenitors

Andrew Groves and to be identified co-writer

In mammals, hair cell regeneration requires the re-activation of developmental genetic programs in mature supporting cells. This chapter discusses what is known about molecular regulation of supporting cell specification during development and the steps by which supporting cells alter their phenotype and form new hair cells after hair cell damage. This chapter will review basic mechanisms of transcriptional regulation of supporting cell and hair cell identity, including what is known about downstream targets of important transcription factors.

Chapter 7. Cell Cycle Regulation in Hair Cell Progenitors

Neil Segil and Ksenia Gdeneva

The acquisition of negative regulation of supporting cell division in the early postnatal period is a major barrier to mammalian hair cell regeneration. This chapter will provide a basic overview of the cell cycle, discussing the molecules and signals (p21, p27, MYC, cyclinD, etc.) that regulate terminal mitosis or cell cycle re-entry in different hair cell epithelia, both during development and after hair cell injury. One part of this chapter will be devoted to how cell cycle regulatory molecules may be manipulated in supporting cells to promote regeneration in future studies.

Chapter 8. Otic Stem Cells

Stefan Heller and to be identified co-writer

Embryonic and induced stem cells are important models for research on hair cell regeneration, and they may serve as therapeutic agents in the future. This chapter will review experiments and techniques leading to the derivation of hair cells from both embryonic and induced pluripotent stems cells. Emphasis will be placed on how such studies contribute to our basic knowledge of hair cell differentiation. The advantages of stem cell-derived 'organoids', which are becoming an important method in basic developmental studies of many tissue types, for hair cell regeneration studies will be considered. Additionally, the authors will discuss the translational promises of stem cell applications approach, as well as the numerous problems that need to be overcome before stem cells can be used therapeutically.

Chapter 9. Neural Regeneration

Steven Green and to be identified co-writer

Neural degeneration following hair cell loss is a major caveat for future therapies employing regeneration or transplantation of hair cells. This chapter will review the responses of auditory and vestibular neurons to hair cell damage in a range of species and address the time-course of ganglion cell degeneration in mammals. It will discuss what is known about the mechanisms controlling innervation of regenerated hair cells, including molecules that promote sprouting and regrowth of surviving neurons in vitro and in vivo. Finally, the chapter will consider how neural stem cells are being employed to study regulation of neuronal survival after de-afferentatation and during hair cell regeneration, and how stem cells are being developed for transplantation studies

Chapter 10. Strategies for Promoting Auditory Hair Cell Regeneration in Mature Mammals

Brandon Cox and to be identified co-writer

This chapter will describe new techniques being applied in regeneration research, with emphasis on gain of function and loss of function tools for gene manipulation in vivo (e.g., CRISPR/Cas and CreLoxP) and methods for gene delivery being applied to the inner ear for gene therapy (adenovirus, siRNA, anti-sense, and microRNAs).

Chapter 11. Emerging Approaches for Understanding Genetic and Epigenetic Regulation of Hair Cell Regeneration

Authors not yet determined

In adult mammals, hair cell regeneration does not occur in the cochlea and it is highly limited in vestibular organs. This chapter addresses modern approaches to identify new molecular regulators of hair cell regeneration in mammals and non-mammals. For instance, in the cochlea, supporting cells from the mouse cochlea retain some regenerative ability at postnatal day 0 (P0), but it is lost over the next postnatal week. This transition is caused by changes in extracellular signaling, transcriptional networks, and epigenetic remodeling in progenitor cells. Although present knowledge is still limited, we expect this field will expand considerably in the near future. This chapter should will how transcriptomics (bulk and single cell) and epigenomics (DNA methylation, chromatin structure) have been applied to study cellular regeneration in our system and in others.