Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells.
Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells.
复制标题
DOI：
10.1016/j.celrep.2017.01.066
复制
发表时间：
2017-02-21
期刊：
影响因子：
8.8
通讯作者：
Edge ASB
中科院分区：
文献类型：
--
作者：
McLean WJ;Yin X;Lu L;Lenz DR;McLean D;Langer R;Karp JM;Edge ASB
耳蜗毛细胞的死亡，不能再生，是导致听力损失的一个原因，在很高的比例的人口。目前，还没有获得大量耳蜗毛细胞的方法。在这里，使用小分子方法，我们显示耳蜗支持细胞表达和维持Lgr 5（一种上皮干细胞标记物）的显著扩增（> 2，000倍），以响应GSK 3 β抑制剂对Wnt信号传导的刺激和组蛋白脱乙酰酶抑制剂的转录激活。表达Lgr 5的细胞以高产量分化成毛细胞。从单个小鼠耳蜗中，我们获得了超过11，500个毛细胞，而在没有诱导的情况下不到200个。新生成的毛细胞具有用于转导、突触形成和特化毛细胞活动的束和分子机制。靶向能够增殖和耳蜗毛细胞替代的支持细胞可能会导致听力损失治疗的发现。耳蜗损伤后产生毛细胞是治疗耳聋的一种潜在方法。姆克林等人证明，在用生长因子和药物的组合处理后，从耳蜗感觉上皮细胞解离的Lgr 5+支持细胞形成类器官并高产率地分化成毛细胞。
Death of cochlear hair cells, which do not regenerate, is a cause of hearing loss in a high percentage of the population. Currently, no approach exists to obtain large numbers of cochlear hair cells. Here, using a small-molecule approach, we show significant expansion (>2,000-fold) of cochlear supporting cells expressing and maintaining Lgr5, an epithelial stem cell marker, in response to stimulation of Wnt signaling by a GSK3β inhibitor and transcriptional activation by a histone deacetylase inhibitor. The Lgr5-expressing cells differentiate into hair cells in high yield. From a single mouse cochlea, we obtained over 11,500 hair cells, compared to less than 200 in the absence of induction. The newly generated hair cells have bundles and molecular machinery for transduction, synapse formation, and specialized hair cell activity. Targeting supporting cells capable of proliferation and cochlear hair cell replacement could lead to the discovery of hearing loss treatments. Generation of hair cells after damage to the cochlea is a potential treatment for deafness. McLean et al. demonstrate that Lgr5+ supporting cells dissociated from the cochlear sensory epithelium form organoids and differentiate into hair cells in high yield after treatment with a combination of growth factors and drugs.