Replacement of the cochlear sensory epithelium using stem cell-derived inner ear organoids

使用干细胞衍生的内耳类器官替代耳蜗感觉上皮

• 批准号: 10543411
• 负责人: ROBERT K DUNCAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543411
• 关键词: 3-Dimensional; Adult; Affect; Aging; Animals; Area; Auditory; Auditory Brainstem Responses; Auditory Perception; Auditory Threshold; Biological; Biological Response Modifier Therapy; Cavia; Cell Differentiation process; Cell Maturation; Cell Survival; Cells; Chronic; Cochlea; Cochlear Implants; Cochlear duct; Complex; Contralateral; Craniocerebral Trauma; Cuboidal Epithelium; Data; Development; Devices; Ear; Engraftment; Environment; Epithelial Cells; Epithelium; Evaluation; Experimental Implants; Extracellular Matrix; Generations; Government; Hair Cells; Harvest; Histologic; Human; Implant; In Vitro; Injury; Labyrinth; Liquid substance; Longitudinal Studies; Maintenance; Mammals; Measurement; Methods; Mus; Natural regeneration; Organ of Corti; Organoids; Otic Vesicle; Performance; Pluripotent Stem Cells; Preparation; Protocols documentation; Recording of previous events; Refractory; Rehabilitation therapy; Replacement Therapy; Reporting; Research; Role; Sensorineural Hearing Loss; Sensory; Sensory Hair; Series; Severities; Specific qualifier value; Stromal Cells; Supporting Cell; Suspensions; Technology; Temporal bone structure; Testing; Tight Junctions; Tissues; Vesicle; Veterans; cell type; comparative efficacy; conditioning; cost; deaf; deafening; embryonic stem cell; experimental study; genetic approach; hearing impairment; hearing restoration; implantation; improved; in vivo; injured; matrigel; method development; military veteran; mosaic; noise exposure; normal hearing; older patient; progenitor; psychologic; restoration; social; stem cell biology; stem cell therapy; stem cells; three dimensional cell culture; transdifferentiation; treatment choice

ABSTRACT Sensorineural hearing loss is highly prevalent in military Veterans, but there is currently no biological treatment enabling full restoration of the cochlea and hearing perception. Hearing restoration by stem cell therapy holds great promise. New advances in the generation of inner ear organoids from pluripotent stem cells and our pioneering efforts to condition the cochlea for receiving foreign cells have paved the way forward. However, there remain several major obstacles to combining these approaches. Foremost, there is a lack of a coherent strategy for identifying the right donor cells and tailoring these to the severity of injury in the cochlea. In this proposal, we are focused on stem cell therapy for the severely damaged cochlea, where extreme or chronic injury has reduced the organ of Corti to a flat epithelium of stromal cells that have so far proven refractory to genetic approaches to regeneration. This approach may be the only viable strategy for restoring the full sensory epithelium in older Veterans with long-term hearing loss. Protocols for developing inner ear organoids from pluripotent stem cells produce potential donor cells all along the otic developmental trajectory. Notably, we have developed methods to isolate otic vesicle progenitors from non-otic cells in these cultures, but maturation of the vesicles into sensory epithelia requires a complex, commercial extracellular matrix for efficient differentiation in vitro. In this proposal, we test the hypothesis that multipotent otic progenitors will be required to replace both hair cells and supporting cells in the severely damaged cochlea. The proposal tests the impact of implanting donor cells at various stages of differentiation and examines the role of the extracellular matrix in promoting donor cell survival and maturation. Successful completion of these studies will open new paths toward a viable biological treatment for severe hearing loss.

摘要