Regeneration of the cochlear cells by bone marrow stem cells

骨髓干细胞再生耳蜗细胞

基本信息

批准号：
14571648
负责人：
IWAI Hiroshi
金额：
$ 2.18万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

The aim of the current study was to evaluate function of hemopoietic stem cells (HSCs) or immunocompetent cells differentiated from those stem cells in regeneration or degeneration of the cochlear cells associated with age-related sensorineural hearing loss (SNHL).As animal models of accelerated age-related SNHL, two murine substrains, the MRL/lpr mouse and SAMP1 mouse were used. As normal mice which show slow presbycusis, BALB/c, C57BL/6, or GFP (green fluorescence protein) mice which is C57BL/6 transgenic mice with GFP DNA were used.Bone marrow cells including HSCs were inoculated intravenously as conventional bone marrow transplantation (BMT), or into bone marrow cavity (intra-BMT) which can maintain the host immune function similar to the function of pre-transplantation.The results indicated that SNHL and cochlear degeneration in both animal models do not result from defects in the cochlea but do from defects in HSCs and immunocompetent cells derived from the HSCs because transplan … More tation of bone marrow from normal mice prevented or recovered the SNHL with degeneration of the stria vascularis in MRL/lpr mice, or of the spiral ganglion (SG) cells in SAMP1 mice, and also because transplantation of bone marrow from the murine models of SNHL with cochlear pathology caused the same hearing loss and pathology in the normal mice.The relationship between presbycusis and the immune system was also analyzed using SAMP1 mice. When the immune functions were impaired, these mice showed aggressive development of SNHL and degeneration of the SG. These findings indicate that not only the gene backgrounds but also immune functions affect the neurogeneration system in SAMP1 mice.Immunofluorescence study indicated that donor cells including HSCs and immunocompetent cells were not observed in the cochlea of the SNHL mice which had been transplanted bone marrow cells from the GEP mice and prevented SNHL and degeneration of the cochlea. In addition, both MRL/lpr and SAMP1 mice showed age-related dysfunctions of Th cells. These findings taken together indicate that cochlear cells are not regenerated or maintained by local infiltrated cells including HSCs and immunocompetent cells but are managed by humoral factors, through the blood-inner ear barrier, such as cytokines released by systemic Th cells, which may play key role of therapy for chronic development of SNHL. Less

当前研究的目的是评估造血干细胞（HSC）或从这些干细胞分化的免疫活性细胞在与年龄相关的感音神经性听力损失（SNHL）相关的耳蜗细胞再生或退化中的功能。使用两种小鼠亚系：MRL/lpr小鼠和SAMP1小鼠作为与年龄相关的SNHL，BALB/c作为表现出缓慢老年性耳聋的正常小鼠。使用 C57BL/6 或 GFP（绿色荧光蛋白）小鼠，其为具有 GFP DNA 的 C57BL/6 转基因小鼠。包括 HSC 在内的骨髓细胞按照常规骨髓移植（BMT）静脉内接种，或接种到骨髓腔（骨髓腔内）。 BMT）可维持宿主免疫功能与移植前相似。结果表明，两种动物模型中的SNHL和耳蜗变性并非由免疫缺陷引起。但由于 HSC 和 HSC 衍生的免疫活性细胞的缺陷，正常小鼠的骨髓移植可预防或恢复 SNHL，并伴有 MRL/lpr 小鼠血管纹或螺旋神经节 (SG) 的变性SAMP1 小鼠中的细胞，并且还因为从具有耳蜗病理学的 SNHL 小鼠模型移植骨髓导致了正常小鼠中相同的听力损失和病理学。还使用 SAMP1 小鼠对老年性聋和免疫系统之间的关系进行了分析，当免疫功能受损时，这些小鼠表现出 SNHL 的严重发展和 SG 的退化。这些发现表明，不仅基因背景而且免疫功能也会影响神经生成系统。免疫荧光研究表明，移植了GEP小鼠骨髓细胞的SNHL小鼠的耳蜗中没有观察到包括HSC和免疫活性细胞在内的供体细胞。此外，MRL/lpr 和 SAMP1 小鼠均表现出与年龄相关的 Th 细胞功能障碍，这些发现共同表明耳蜗细胞不是由局部浸润细胞（包括 HSC 和免疫活性细胞）再生或维持的。由体液因子通过血液-内耳屏障进行管理，例如全身性 Th 细胞释放的细胞因子，这可能在 SNHL 慢性发展的治疗中发挥关键作用。