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

先天性耳聋的发病率约为千分之一，其中一半有遗传背景，如Connexin 26基因突变。目前还没有研究出挽救这种遗传性耳聋的策略。近年来，已有大量细胞治疗的临床研究报道，并在临床上用于治疗多种疑难杂症。也已使用一些实验室动物研究了感音神经性耳聋的内耳细胞疗法，尽管伴随着正常功能细胞的补充以及组织修复、细胞/分子功能的恢复，听力恢复的成功报道仍然很少。在此之前，我们开发了一种新的动物模型，急性感音神经性听力损失由于纤维细胞功能障碍和骨髓间充质干细胞（MSC）进行细胞治疗作为补充耳蜗纤维细胞功能的耳蜗离子运输。与胚胎干细胞相比， ...更多信息 干（ES）细胞和诱导多能干（iPS）细胞。我们将MSC注射到外半规管中，然后在外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位点的机制，发现单核细胞趋化蛋白1（MCP 1）和趋化因子（C-C基序）受体2（CCR 2）在这种细胞诱导中起重要作用。为了增强耳蜗中MSC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MCP 1的表达和在MSC中强制表达CCR 2。此外，我们建立了一种新的人类最常见的遗传性耳聋Connexin 26突变的小鼠模型。利用这些动物模型，开发的干细胞和新的策略，以加强干细胞诱导，我们研究建立一个有效的干细胞治疗耳蜗靶点，随后恢复听力功能的遗传性耳聋。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