The Neuroregenerative Capacity of Olfactory Stem Cells Is Not Limitless: Implications for Aging
The Neuroregenerative Capacity of Olfactory Stem Cells Is Not Limitless: Implications for Aging
复制标题
DOI：
10.1523/jneurosci.3261-17.2018
复制
发表时间：
2018-08-01
影响因子：
5.3
通讯作者：
Jang, Woochan
中科院分区：
文献类型：
--
作者：
Child, Kevin M.;Herrick, Daniel B.;Jang, Woochan
脊椎动物的嗅上皮（OE）是高度再生的神经上皮，其在正常条件下由干细胞和祖细胞群体、球状基底细胞（GBC）维持，其也有助于损伤后的上皮重建。然而，OE的老化往往导致神经源性衰竭，GBC和嗅觉感觉神经元（OSN）的消失。非神经元组织可能仍然是嗅觉器官，具有不间断的顶面排列的微绒毛覆盖的支持细胞，或者可能发生呼吸道化生。我们已经产生了一个转基因小鼠模型的神经源性衰竭使用嗅觉标志物蛋白驱动的Tet-off调节白喉毒素的A亚基，使成熟的OSN的死亡加速。早在2个月大时，转基因小鼠的上皮细胞，无论性别如何，都重现了在人类和啮齿动物的老年OE中所看到的。上皮区域完全缺乏神经元和GBC;而水平基底细胞（储备干细胞群）没有显示出激活的证据。令人惊讶的是，其他区域的嗅觉发生呼吸化生。还检查了加速神经元死亡和神经支配减少对嗅球（OB）的影响。恒定的神经元更新使肾小球萎缩，并影响肾小球周围层的多巴胺能中间神经元。此外，在一些GBC持续存在的地区，OSN死亡的加速可以逆转。然而，投射到OB恢复不完全，神经支配的肾小球明显改变。因此，当GBC消失时，OE再生的能力会减弱。
The olfactory epithelium (OE) of vertebrates is a highly regenerative neuroepithelium that is maintained under normal conditions by a population of stem and progenitor cells, globose basal cells (GBCs), which also contribute to epithelial reconstitution after injury. However, aging of the OE often leads to neurogenic exhaustion, the disappearance of both GBCs and olfactory sensory neurons (OSNs). Aneuronal tissue may remain as olfactory, with an uninterrupted sheet of apically arrayed microvillar-capped sustentacular cell, or may undergo respiratory metaplasia. We have generated a transgenic mouse model for neurogenic exhaustion using olfactory marker protein-driven Tet-off regulation of the A subunit of Diphtheria toxin such that the death of mature OSNs is accelerated. At as early as 2 months of age, the epithelium of transgenic mice, regardless of sex, recapitulates what is seen in the aged OE of humans and rodents. Areas of the epithelium completely lack neurons and GBCs; whereas the horizontal basal cells, a reserve stem cell population, show no evidence of activation. Surprisingly, other areas that were olfactory undergo respiratory metaplasia. The impact of accelerated neuronal death and reduced innervation on the olfactory bulb (OB) was also examined. Constant neuronal turnover leaves glomeruli shrunken and affects the dopaminergic interneurons in the periglomerular layer. Moreover, the acceleration of OSN death can be reversed in those areas where some GBCs persist. However, the projection onto the OB recovers incompletely and the reinnervated glomeruli are markedly altered. Therefore, the capacity for OE regeneration is tempered when GBCs disappear.