Stem Cell Regeneration of Human Spiral Ganglion Neurons Toward Hearing Restoration
Abstract
Rationale for the research: Hearing loss is a major concern of military personnel, who are exposed to loud explosions and working environments that damage the cochlea, the small inner-ear organ that converts sound to neural impulses. For severe hearing losses, the cochlear implant (CI) is the preferred remedy. CIs bring awareness of a person s sound environment and speech perception. However, users struggle with hearing speech in noise, appreciating music, and understanding emotion and intonation of speech. Also, advances in CI performance have plateaued, indicating the need for new efforts. Fortunately, there are known problems that point to new "biohybrid" CI designs that combine bio-active components and proven CI technology. Damaged auditory nerve fibers (ANFs) -- which transmit information from cochlea to brain -- lack the axons that get close to CI electrodes. Lacking those intimate contacts, each CI electrode excites relatively large ANF groups, reducing the ability to transmit many channels of sound information and resulting in rather crude auditory perceptions. Goals and objectives: We want to advance CI performance by adding more neuronal channels to the damaged cochlea so that each CI electrode excites a smaller number of ANFs. That is, we want to close the gap between CI electrodes and surviving ANFs to increase the amount of detail transmitted to the brain. Thus, our long-term goal is a "biohybrid CI" that combines well-tested CI designs with newly transplanted ANFs derived from human stem cells (which we call "derived ANFs"). We have done the work to convert human pluripotent stem cells into derived ANFs and have transplanted derived ANFs into animal models. However, we seek to transplant the cells into the same cochlear compartment where CIs are placed (i.e., the scala tympani), so that they can extend new neural processes to the surviving ANFs, bridging the gaps and improving CI performance. Our short-term goals will be conducted within a 3-year plan and directed toward overcoming roadblocks to this biohybrid CI vision. We will study the benefits of (1) packaging derived ANFs as three-dimension multicellular aggregates (known to enhance survival), (2) providing a supportive extracellular support matrix, and (3) infusion of proteins in promoting neuronal survival, neurite outgrowth, and connectivity to extant ANFs, all key milestones to the development of the biohybrid CI. This work will be done within cell cultures and in animal models. Ultimate applicability of this research: The biohybrid CI will benefit all future CI candidates as it is expected to work better than existing CIs. As a result, the patient pool would be expanded, benefitting more people. Benefits: One near-term benefit will be advancing the biohybrid CI design by tackling key roadblocks. Our results will also benefit researchers looking beyond the ear, as survival and integration of stem cell-derived neurons are broad concerns. As our approach "piggybacks" on the proven CI, there is no need to work out a new surgical approach. Our success will motivate CI manufacturers to design better CIs with more electrodes so as to provide users with more detailed acoustic experiences, with better speech and music perception. Our work provides interim benefits essential to the safe and effective application of the biohybrid CI to human patients. Risks: Stem cell replacement therapies bring up a concern of teratoma formation; however, our approach eliminates it by using derived ANFs past the cell-division stage. While the inner ear may be thought of an immune privileged organ, immunorejection can be prevented by suppressant drugs and also through the promising use of "induced pluripotent stem cells" from the recipient, which do not evoke an immune response. Translational efforts: We advance translational efforts through interim outcomes that will improve the survival and integration of stem cell-derived ANFs transplanted into the cochlea, ther
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810752
Entities
People
- Akihiro J Matsuoka
Organizations
- Northwestern University
- United States Army