Cell therapy targeting cochlear fibrocyte of Brn-4 deficient mouse with bone marrow mesenchymal stem cell

先天性耳聋患儿约为千分之一，其中半数具有Connexin26基因突变等遗传背景。抢救这种遗传性耳聋的策略尚未制定出来。近年来，一些关于细胞疗法的临床研究已被报道，并在临床上用于治疗一些难治性疾病。内耳细胞治疗感音神经性听力损失也有实验动物研究，虽然在补充正常功能细胞并进行组织修复的同时恢复听力的成功报道，但恢复细胞/分子功能的报道仍然很少。在此之前，我们开发了一种新型的由纤维细胞功能障碍引起的急性感音神经性听力损失动物模型，并使用骨髓间充质干细胞（MSC）作为耳蜗纤维细胞的补充进行细胞治疗。与胚胎干细胞（ES）和诱导多能干细胞（iPS）相比，间充质干细胞的致癌风险较小。我们将MSC注入外侧半规管，然后在侧壁的损伤区域检测到一些干细胞。移植动物的听力恢复率明显高于对照组。我们分析了这种干细胞诱导到耳蜗靶点的机制，发现单核细胞趋化蛋白1 （MCP1）和趋化因子（C-C motif）受体2 （CCR2）在这种细胞诱导中发挥了重要作用。为了增强MSC在耳蜗中的诱导，我们开发了一种新的移植策略，通过诱导宿主耳蜗组织中MCP1的表达和MSC中CCR2的强制表达。此外，我们还建立了一种新的小鼠模型来研究人类最常见的遗传性耳聋——Connexin26突变。利用这些动物模型、已开发的干细胞和增强干细胞诱导的新策略，我们试图建立一种有效的干细胞治疗遗传性耳聋耳蜗靶部位并恢复听力功能的方法。少

Congenital deafness affects about 1 in 1000 children and the half of them have genetic background such as Connexin26 gene mutation. The strategy to rescue such heredity deafness has not been developed yet. Recently, a number of clinical studies for cell therapy have been reported and clinically used for several intractable diseases. Inner ear cell therapy for sensorineural hearing loss also has been studied using some laboratory animals, although the successful reports for the hearing recovery accompanied with supplementation of the normal functional cells followed by tissue repair, recovery of the cellular/molecular functions were still few. Previously, we developed a novel animal model for acute sensorineural hearing loss due to fibrocyte dysfunction and performed cell therapy with bone marrow mesenchymal stem cells (MSC) as supplementation of cochlear fibrocytes functioning for cochlear ion transport. MSC has been known to have little risk for carcinogenesis compared with embryonic … More stem (ES) cell and induced pluripotent stem (iPS) cell. We injected MSC into the lateral semicircular canal and a number of these stem cells were then detected in the injured area in the lateral wall. The transplanted animals showed a significantly higher hearing recovery ratio than controls. We analyzed the machinery of this stem cell induction to the targeted site in cochlea and found that monocyte chemotactic protein 1 (MCP1) and chemokine (C-C motif) receptor 2 (CCR2) played important roles for this cell induction. To enhance the MSC induction in cochlea, we developed a novel transplant strategy by induction of MCP1 expression in host cochlear tissue and forced expression of CCR2 in MSC. Furthermore, we developed a novel mouse model for Connexin26 mutation as most frequent heredity deafness in human. With these animal models, the developed stem cells and the novel strategy to enhance the stem cell induction, we examined to establish an efficient stem cell therapy to cochlear target site followed by recovery of hearing function in heredity deafness. Less