Building an Artificial Stem Cell Niche: Prerequisites for Future 3D‐Formation of Inner Ear Structures—Toward 3D Inner Ear Biotechnology

Abstract

In recent years, there has been an increased interest in stem cells for the purpose of regenerative medicine to deliver a wide range of therapies to treat many diseases. However, two‐dimensional cultures of stem cells are of limited use when studying the mechanism of pathogenesis of diseases and the feasibility of a treatment. Therefore, research is focusing on the strengths of stem cells in the three‐dimensional (3D) structures mimicking organs, that is, organoids, or organ‐on‐chip, for modeling human biology and disease. As 3D technology advances, it is necessary to know which signals stem cells need to multiply and differentiate into complex structures. This holds especially true for the complex 3D structure of the inner ear. Recent work suggests that although other factors play a role, the extracellular matrix (ECM), including its topography, is crucial to mimic a stem cell niche in vitro and to drive stem cells toward the formation of the tissue of interest. Technological developments have led to the investigation of biomaterials that closely resemble the native ECM. In the fast forward moving research of organoids and organs‐on‐chip, the inner ear has hardly received attention. This review aims to provide an overview, by describing the general context in which cells, matrix and morphogens cooperate in order to build a tissue, to facilitate research in 3D inner ear technology. Anat Rec, 303:408–426, 2020. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Application of Mesenchymal Stem Cell Therapy and Inner Ear Regeneration for Hearing Loss: A Review

“…Similarly, the ECM is crucial in mimicking a stem cell niche in vitro and in driving stem cells toward the three dimensions formation. Technological developments have led to the investigation of biomaterials similar to the native ECM [56].…”

Back to the Future: From Appendage Development Toward Future Human Hair Follicle Neogenesis

“…Moreover, in contrast to natural scaffolds, synthetic ECM proteins have little batch-to-batch composition variation, and have a reduced risk for pathogen contamination (Dawson et al, 2008;Ghasemi-Mobarakeh et al, 2015). It is important to note that Matrigel R is mouse-derived and due to its batch-to-batch variation and undefined growth factors, it is neither safe nor practical for human studies (de Groot et al, 2020).…”

“…A relatively new method to create ECM scaffolds is self-assembling peptide hydrogels formed by RADA-16. One major advantage of RADA-16 over other synthetic scaffolds is the diameter of the microfibers, which is approximately 10 nm compared to 100 µm for synthetic microfibers (de Groot et al, 2020). When cultured with larger microfiber scaffolds, different cells can only adhere to one large fiber at a time, so the cells are effectively still in a 2D environment (de Groot et al, 2020).…”

“…Moreover, most studies on HF organogenesis have focused on the biomolecular pathways involved and not on achieving HF neogenesis in vitro. In regenerative biology, it is generally acknowledged that matrix molecules, and their physicochemical characteristics, are involved in the control and completion of organogenesis, but this has hardly been explored in the context of HF morphogenesis (de Groot et al, 2020). It is known that signaling pathways required for early HF morphogenesis are evolutionarily conserved between species (Botchkarev et al, 2003;Wu et al, 2004).…”

A Regenerative Medicine Approach to the Treatment of Hearing, Balance, and Olfactory Disorders: What Is in the Future for Otolaryngology?

“…The areas of research covered by these papers are organized into related groups starting with a single paper that addresses historical aspects, that is, “Historical aspects of gene therapy and stem cell therapy in the treatment of hearing and balance disorders” (Van De Water, ). This is followed by a group of six papers that utilized in vitro techniques to examine stem cell growth characteristics, migratory behavior, potential for therapeutic application, and isolation of new stem cells from human inner ear tissue: that is, “Building an artificial stem cell niche: prerequisites for future 3‐D‐formation of inner ear structures toward 3D inner ear biotechnology,” (De Groot et al, ); “Imaging bioluminescent exogenous stem cells in intact guinea pig cochlea,” (Schomann et al, ); “The effect of Matrigel on a human neural progenitor dissociated sphere culture,” (Kaiser et al, ); “Isolation and characterization of mammalian otic stem cells that can differentiate into both sensory and neuronal lineages,” (Kojima et al, ); “Progenitor cells from the human inner ear,” (Senn et al, ); and “Evaluation of cilia function in rat trachea reconstructed using collagen sponge scaffold seeded with adipose tissue‐derived stem cells” (Nakamura et al, ). This series of in vitro studies is followed by a group of five papers that probe the behavior of stem cells in vivo , looking at their ability to treat hearing loss and ultrastructural character of stem cell‐initiated hair cell regeneration: that is, “Bone marrow stromal cells accelerate hearing recovery via regeneration or maintenance of cochlear fibrocytes in mouse spiral ligaments,” (Kada et al, ); “Effect of bone marrow‐derived mesenchymal stem cells on cochlear function in an experimental rat model,” (Mittal et al, ); “Transplantation and tracking of human umbilical cord mesenchymal stem cells labeled with SPIO in deaf pigs,” (Xu et al, ); “Ultrastructural characterization of stem cell‐derived replacement vestibular hair cells within ototoxin‐damaged rat utricle explants,” (Werner et al, ); and “Recent advancements in gene and stem cell‐based treatment modalities: potential applications in noise‐induced hearing loss” (Eshraghi et al, ).…”