Human Hematopoietic Stem Cells and the Aging Inner Ear

在没有噪音或其他耳毒素的情况下，与年龄相关的听力损失主要是退化的结果。 导致代谢性老年性聋的耳蜗中的特定非感觉细胞。与感觉毛细胞不同 不能再生的非感觉细胞，如螺旋韧带中的纤维细胞和神经胶质样细胞 在听觉神经中，能够在受伤后重新繁殖，尽管它们的再生能力似乎 随着年龄的增长而衰退。这些非感觉细胞能够自我修复的机制仍然存在 未知最近的研究表明，骨髓（BM）干细胞有潜力， 分化成多种非造血细胞谱系，但需要注意的是， 在归巢、植入和分化方面有效。我们的研究表明，一些非感官的 成年小鼠中的耳蜗细胞连续地来源于造血干细胞（HSC）。此外，委员会认为， 我们已经证明，HSC衍生细胞在耳蜗外侧壁和听神经中的移植是 纤维细胞和螺旋神经节神经元化学损伤后显著增加。在这里，我们建议 使用人-鼠异种移植模型确定人内耳细胞是否来源于HSC （人源化小鼠）。我们的中心假设是，人类内耳中的某些细胞类型不断地 来源于HSC，HSC老化和耳蜗损伤显著影响干细胞植入， 分化提出了三个具体目标。目标3.1确定人类干细胞的潜力 从脐带血中分离以移植并分化成特定耳蜗细胞类型。目标3.2确定了 来自年轻和老年人受试者的BM干细胞，特别是那些患有代谢性疾病的受试者， 老年性聋，不同的能力，植入和分化的内耳。目标3.3测试了 耳蜗损伤对年轻人和老年人骨髓干细胞移植和分化的影响 科目老年干细胞将从具有正常听力的老年人受试者的BM中分离， 代谢性老年性聋，如通过人类主体核心中的听觉性能测量所确定的。 这个翻译项目将有助于进一步了解BM细胞如何促进细胞增殖。 人类内耳内环境的平衡这些知识将提供所需的知识基础， 设计治疗与年龄相关的听力损失，特别是代谢性老年性聋。

In the absence of noise or other ototoxins, age-related hearing loss is largely the result of the degeneration of specific non-sensory cells in the cochlea resulting in metabolic presbyacusis. Unlike sensory hair cells that are unable to regenerate, non-sensory cells, such as fibrocytes in the spiral ligament and glia-like cells in the auditory nerve, are able to repopulate themselves after injury, although their regenerative ability seems to decline with age. The mechanism whereby these non-sensory cells are able to repair themselves remains unknown. Recent investigations have shown that bone marrow (BM) stem cells have the potential to differentiate into multiple non-hematopoietic cell lineages with the caveat that aged BM stem cells are less effective at homing, engraftment and differentiation. Our studies have documented that some non-sensory cochlear cells in the adult mouse are continually derived from hematopoietic stem cells (HSCs). Moreover, we have shown that engraftment of the HSC-derived cells in the cochlear lateral wall and auditory nerve is significantly increased after fibrocytes and spiral ganglion neurons are chemically injured. Here, we propose to determine whether human inner ear cells are derived from HSCs using human-murine xenograft models (humanized mice). Our central hypotheses are that certain cell types in the human inner ear are continually derived from HSCs, and that HSC aging and cochlear injury significantly affect stem cell engraftment and differentiation. Three specific aims are proposed. Aim 3.1 determines the potential of human stem cells isolated from cord blood to engraft and differentiate into specific cochlear cell types. Aim 3.2 determines the extent to which BM stem cells from younger and older human subjects, especially those with metabolic presbyacusis, differ in their abilities to engraft and differentiate in the inner ear. Aim 3.3 tests the effects of cochlear injury on the engraftment and differentiation of BM stem cells from younger and older human subjects. The aged stem cells will be isolated from the BM of older human subjects with normal hearing and with metabolic presbyacusis as determined by auditory performance measures in the Human Subjects Core. This translational project will help further the understanding of how BM cells contribute to cellular homeostasis in the human inner ear. Such knowledge will provide the intellectual foundation needed to design treatments for age-related hearing loss, especially metabolic presbyacusis.