In vivo proliferative regeneration of balance hair cells in newborn mice.
In vivo proliferative regeneration of balance hair cells in newborn mice.
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DOI：
10.1523/jneurosci.6274-11.2012
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发表时间：
2012-05-09
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影响因子：
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通讯作者：
Corwin JT
中科院分区：
文献类型：
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作者：
Burns JC;Cox BC;Thiede BR;Zuo J;Corwin JT
在非哺乳类脊椎动物中，机械感受性毛细胞在整个生命过程中都会再生，这使它们能够从影响人类和其他哺乳动物的永久性听力和平衡缺陷中恢复。哺乳动物中类似缺陷的不可逆性仍未得到解释，但通常归因于细胞生成在胚胎期急剧下降。然而，最近的研究结果表明，小鼠椭圆囊中的重力感应毛细胞在新生儿发育过程中数量可能会增加，这增加了幼鼠可能保留足够的细胞可塑性以进行有丝分裂毛细胞再生的可能性。为了验证这一点，我们使用新霉素杀死不同年龄小鼠培养的椭圆囊中的毛细胞，发现最年幼的新生小鼠受损椭圆囊中的增殖增加了十倍。为了在体内杀死毛细胞，我们构建了一种新型小鼠模型，该模型使用一种可诱导的、毛细胞特异性的CreER等位基因来驱动白喉毒素A片段（DTA）的表达。在新生小鼠中，诱导DTA表达会杀死毛细胞，并导致体内显著的有丝分裂毛细胞替代，这种替代发生在产生毛细胞的发育性有丝分裂正常停止数天之后。在5日龄小鼠中诱导DTA表达也会导致毛细胞丢失，但不再引发有丝分裂毛细胞替代。这些发现表明，在哺乳动物平衡上皮的支持细胞分化出独特的细胞学特征并失去可塑性的产后时期，体内会出现再生限制，并且它们支持这样一种观点，即这些细胞的分化可能直接抑制再生或消除一个重要但尚未确定的干细胞库。
The regeneration of mechanoreceptive hair cells occurs throughout life in non-mammalian vertebrates and allows them to recover from hearing and balance deficits that affect humans and other mammals permanently. The irreversibility of comparable deficits in mammals remains unexplained, but often has been attributed to steep embryonic declines in cellular production. However, recent results suggest that gravity-sensing hair cells in murine utricles may increase in number during neonatal development, raising the possibility that young mice might retain sufficient cellular plasticity for mitotic hair cell regeneration. To test for this we used neomycin to kill hair cells in utricles cultured from mice of different ages and found that proliferation increased ten-fold in damaged utricles from the youngest neonates. To kill hair cells in vivo, we generated a novel mouse model that uses an inducible, hair-cell-specific CreER allele to drive expression of diptheria toxin fragment A (DTA). In newborns, induction of DTA expression killed hair cells and resulted in significant, mitotic hair cell replacement in vivo, which occurred days after the normal cessation of developmental mitoses that produce hair cells. DTA expression induced in five-day-old mice also caused hair cell loss, but no longer evoked mitotic hair cell replacement. These findings show that regeneration limits arise in vivo during the postnatal period when the mammalian balance epithelium’s supporting cells differentiate unique cytological characteristics and lose plasticity, and they support the notion that the differentiation of those cells may directly inhibit regeneration or eliminate an essential, but as yet unidentified pool of stem cells.