Stem/Progenitor Cells Derived from the Cochlear Sensory Epithelium Give Rise to Spheres with Distinct Morphologies and Features
Stem/Progenitor Cells Derived from the Cochlear Sensory Epithelium Give Rise to Spheres with Distinct Morphologies and Features
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DOI：
10.1007/s10162-009-0161-3
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发表时间：
2009-06-01
影响因子：
2.4
通讯作者：
Heller, Stefan
中科院分区：
文献类型：
--
作者：
Diensthuber, Marc;Oshima, Kazuo;Heller, Stefan
非哺乳类脊椎动物通过支持细胞的不对称分裂再生失去的感觉毛细胞。因此，鸟类、两栖动物和鱼类的内耳或侧线支持细胞可作为真正的干细胞，导致毛细胞承载器官的高再生能力。毛细胞再生在哺乳动物耳蜗中不发生，但具有增殖能力的细胞可以从新生儿耳蜗中分离出来。当在非粘附条件下培养时，这些细胞具有形成克隆漂浮集落（所谓的球体）的能力。我们注意到，来自小鼠耳蜗感觉上皮细胞的球体群体是异质的，由形态学上不同的球体类型组成，据此分为实心、过渡和空心。耳蜗感觉上皮来源的干/祖细胞最初产生小的实心球体，随后过渡成空心球体，这种变化伴随着大多数球体细胞的上皮分化。只有实心球，在较小程度上，过渡球，似乎窝藏自我更新的干细胞，而空心球不能一贯繁殖。实心球比空心球含有显著更快循环的Pax-2表达推定的耳祖细胞。胰岛-1在新生感觉斑中上调，在实心球中比空心球中更丰富。同样，毛细胞样细胞，其特征在于多种毛细胞标志物的表达，分化的细胞群体中来自固体球显着更高的数字。我们的结论是，耳蜗感觉上皮细胞群最初产生的小实心球，具有自我更新能力，然后再转化为空心球，这是一个过程，伴随着损失的干性和降低的能力，自发地产生毛细胞样细胞。因此，实心球可能代表了最适合用于基于细胞的测定或旨在开发细胞替代疗法的动物模型移植研究的球类型。
Nonmammalian vertebrates regenerate lost sensory hair cells by means of asymmetric division of supporting cells. Inner ear or lateral line supporting cells in birds, amphibians, and fish consequently serve as bona fide stem cells resulting in high regenerative capacity of hair cell-bearing organs. Hair cell regeneration does not happen in the mammalian cochlea, but cells with proliferative capacity can be isolated from the neonatal cochlea. These cells have the ability to form clonal floating colonies, so-called spheres, when cultured in nonadherent conditions. We noticed that the sphere population derived from mouse cochlear sensory epithelium cells was heterogeneous, consisting of morphologically distinct sphere types, hereby classified as solid, transitional, and hollow. Cochlear sensory epithelium-derived stem/progenitor cells initially give rise to small solid spheres, which subsequently transition into hollow spheres, a change that is accompanied by epithelial differentiation of the majority of sphere cells. Only solid spheres, and to a lesser extent, transitional spheres, appeared to harbor self-renewing stem cells, whereas hollow spheres could not be consistently propagated. Solid spheres contained significantly more rapidly cycling Pax-2-expressing presumptive otic progenitor cells than hollow spheres. Islet-1, which becomes upregulated in nascent sensory patches, was also more abundant in solid than in hollow spheres. Likewise, hair cell-like cells, characterized by the expression of multiple hair cell markers, differentiated in significantly higher numbers in cell populations derived from solid spheres. We conclude that cochlear sensory epithelium cell populations initially give rise to small solid spheres that have self-renewing capacity before they subsequently convert into hollow spheres, a process that is accompanied by loss of stemness and reduced ability to spontaneously give rise to hair cell-like cells. Solid spheres might, therefore, represent the most suitable sphere type for cell-based assays or animal model transplantation studies aimed at development of cell replacement therapies.