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很大程度上是退化的结果 耳蜗内特定的非感觉细胞导致代谢性老聋。与感觉性毛细胞不同 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 在听神经中，能够在受伤后重新填充自己，尽管他们的再生能力似乎 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，骨髓干细胞具有潜在的 分化为多种非造血细胞系，但要注意老化的骨髓干细胞较少 在归位、植入和分化方面有效。我们的研究证明，一些非感官的 成年小鼠的耳蜗细胞不断地来源于造血干细胞(HSCs)。此外， 我们已经证明，HSC来源的细胞在耳蜗侧壁和听神经中的植入是 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 利用人-鼠异种移植模型确定人内耳细胞是否来源于造血干细胞 (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是连续的 HSC的衰老和耳蜗损伤显著影响干细胞的植入和 差异化。提出了三个具体目标。Aim 3.1确定人类干细胞的潜力 从脐带血中分离出来并植入体内，并分化为特定类型的耳蜗细胞。AIM 3.2决定了 来自年轻人和老年人的骨髓干细胞的程度，特别是那些有代谢性疾病的人 老年性耳聋患者在内耳植入和分化的能力不同。AIM 3.3测试了 耳蜗伤对青年和老年人骨髓干细胞植入和分化的影响 研究对象。老化的干细胞将从听力正常的老年人的骨髓中分离出来，并 由人类受试者核心中的听觉表现测量确定的代谢性老年性耳聋。 这一翻译项目将有助于进一步了解骨髓细胞如何为细胞 人类内耳的动态平衡。这些知识将提供所需的智力基础 设计年龄相关性听力损失的治疗方法，特别是代谢性老年性耳聋。

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.