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 感音神经性听力损失在退伍军人中非常普遍，但目前没有生物治疗方法 能够完全恢复耳蜗和听觉感知。干细胞疗法可恢复听力 伟大的承诺。利用多能干细胞生成内耳类器官的新进展以及我们的研究 调节耳蜗接受外来细胞的开创性努力已经铺平了道路。然而， 结合这些方法仍然存在几个主要障碍。首先，缺乏连贯性 确定正确的供体细胞并根据耳蜗损伤的严重程度调整这些细胞的策略。在这个 提案中，我们专注于对严重受损的耳蜗进行干细胞治疗，耳蜗严重受损或慢性受损 损伤已将柯蒂氏器官缩小为扁平的基质细胞上皮，迄今为止已证明这种基质细胞难以抵抗 再生的遗传方法。这种方法可能是恢复全面恢复的唯一可行策略。 长期听力损失的老年退伍军人的感觉上皮。开发内耳类器官的方案 多能干细胞沿着耳发育轨迹产生潜在的供体细胞。尤其， 我们已经开发出从这些培养物中的非耳细胞中分离耳囊祖细胞的方法，但是 囊泡成熟为感觉上皮需要复杂的商业细胞外基质 体外有效分化。在这个提议中，我们测试了多能耳祖细胞将是的假设 需要替换严重受损的耳蜗中的毛细胞和支持细胞。提案测试 植入供体细胞在不同分化阶段的影响并检查其作用 细胞外基质促进供体细胞存活和成熟。成功完成这些研究将 为严重听力损失的可行生物治疗开辟新途径。