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.

抽象的 在退伍军人中，感觉神经性听力损失非常普遍，但目前尚无生物治疗 能够完全恢复耳蜗和听力感知。通过干细胞疗法的听力修复 伟大的承诺。从多能干细胞和我们 为了调节接收外国细胞的耳蜗的开创性努力已铺平了前进的方向。然而， 结合这些方法仍然存在几个主要障碍。最重要的是，缺乏连贯的 识别合适的供体细胞并根据耳蜗损伤的严重程度而定制这些供体细胞的策略。在这个 提案，我们专注于严重受损的耳蜗的干细胞疗法，其中极端或慢性 损伤使皮尔蒂的器官降低到迄今已证明难治性的基质细胞的平坦上皮 遗传方法的再生方法。这种方法可能是恢复完整的唯一可行策略 长期听力损失的老年退伍军人的感觉上皮。开发内耳类器官的协议 从多能干细胞中产生沿着耳朵发育轨迹的潜在供体细胞。尤其， 我们已经开发了这些培养物中非色调细胞的耳囊子祖细胞分离的方法，但是 将囊泡成熟到感觉上皮需要一个复杂的商业细胞外基质 在体外有效分化。在此提案中，我们检验了多能类耳祖细胞的假设 需要在严重受损的耳蜗中替换两个细胞和支撑细胞。提案测试 在分化的各个阶段植入供体细胞的影响，并研究了 促进供体细胞存活和成熟的细胞外基质。这些研究的成功完成将 开辟新的途径，通向可行的生物学治疗，以实现严重的听力损失。