Ladrech Sabine, Wang Jing, Simonneau Lionel, Puel Jean-Luc, Lenoir Marc
INSERM, U.583, Laboratoire de Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Montpellier, France.
J Neurosci Res. 2007 Jul;85(9):1970-9. doi: 10.1002/jnr.21335.
Transdifferentiation of nonsensory supporting cells into sensory hair cells occurs naturally in the damaged avian inner ear. Such transdifferentiation was achieved experimentally in the cochlea of deaf guinea pigs through Atoh 1 gene transfection. Supporting cells may therefore serve as targets for transdifferentiation therapy. Supporting cells rapidly degenerate after hair cell disappearance, however, limiting the therapeutic window for gene transfer. We studied the time course of ultrastructural and phenotypical changes occurring in Deiters cells (hair cell supporting cells) after ototoxic treatment in the rat. The presence of macrophages in the cochlea was also investigated, to study any deleterious effects they may have on pathologic tissues. One week after treatment most hair cells had disappeared. Deiters cells no longer expressed the glial marker vimentin but instead displayed typical hair cell markers, the calcium binding proteins calbindin and parvalbumin. This suggests that a process of transdifferentiation of Deiters cells into hair cells was activated. By 3 weeks post-treatment, however, the Deiters cells began to degenerate and by 10 weeks post-treatment the organ of Corti was degraded fully. Interestingly, a marked increase in macrophage density was seen after the end of amikacin treatment to 10 weeks post-treatment. This suggests chronic inflammation is involved in epithelium degeneration. Consequently, early treatments with anti-inflammatory factors might promote supporting cell survival, thus improving the efficacy of more specific strategies aimed to regenerate hair cells from nonsensory cells.
在受损的鸟类内耳中，非感觉支持细胞向感觉毛细胞的转分化自然发生。通过Atoh 1基因转染，在耳聋豚鼠的耳蜗中通过实验实现了这种转分化。因此，支持细胞可能成为转分化治疗的靶点。然而，毛细胞消失后支持细胞会迅速退化，限制了基因转移的治疗窗口。我们研究了大鼠耳毒性治疗后Deiters细胞（毛细胞支持细胞）超微结构和表型变化的时间进程。还研究了耳蜗中巨噬细胞的存在情况，以研究它们可能对病理组织产生的任何有害影响。治疗一周后，大多数毛细胞消失。Deiters细胞不再表达神经胶质标志物波形蛋白，而是显示出典型的毛细胞标志物，即钙结合蛋白钙结合蛋白和小清蛋白。这表明Deiters细胞向毛细胞的转分化过程被激活。然而，治疗后3周，Deiters细胞开始退化，治疗后10周，柯蒂氏器完全退化。有趣的是，在阿米卡星治疗结束后至治疗后10周，巨噬细胞密度显著增加。这表明慢性炎症参与了上皮细胞的退化。因此，用抗炎因子进行早期治疗可能会促进支持细胞的存活，从而提高旨在从非感觉细胞再生毛细胞的更具体策略的疗效。
