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

每1000名儿童中约有1名患有先天性耳聋，其中一半儿童有遗传背景，如连接蛋白26基因突变。拯救这种遗传性耳聋的策略还没有开发出来。最近，一些细胞疗法的临床研究已被报道并临床用于几种顽固性疾病。内耳细胞治疗感音神经性耳聋也已在一些实验动物身上进行了研究，虽然在补充正常功能细胞和组织修复的同时，听力恢复的成功报道仍然很少，但细胞/分子功能的恢复仍然很少。之前，我们建立了一种新的纤维细胞功能障碍所致的急性感音神经性听力损失的动物模型，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。已经知道，与胚胎…相比，骨髓间充质干细胞致癌的风险很小。更多的干细胞(ES)和诱导的多能干细胞(IPS)。我们将MSC注射到外侧半规管内，然后在损伤的侧壁区域检测到许多干细胞。移植动物的听力恢复率明显高于对照组。我们分析了干细胞向耳蜗靶向诱导的机制，发现单核细胞趋化蛋白1(MCP1)和趋化因子(C-C基序)受体2(CCR2)在这种细胞诱导中起着重要作用。为了促进MSC在耳蜗内的诱导，我们开发了一种新的移植策略，即在宿主耳蜗组织中诱导MCP1的表达，并在MSC中强制表达CCR2。此外，我们开发了一种新的小鼠模型，用于检测人类最常见的遗传性耳聋--连接蛋白26突变。通过这些动物模型、已开发的干细胞和促进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方法，以期在遗传性耳聋的耳蜗靶部位建立一种有效的干细胞治疗方法，继而恢复听力功能。较少

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