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八、甲状腺干细胞

干细胞是未分化细胞,能够自我更新和分化成一种或多种功能的细胞。“成体”干细胞,通常称为“祖细胞”,只能分化为它们所在的器官特异性的细胞型。一些器官有成体干细胞的存在,其在疾病或损伤后的修复中起着关键作用。虽然许多年前就假设甲状腺干/祖细胞的存在 [36] ,但近几年才在成人甲状腺中找到支持的证据。

首先在骨髓中发现一群叫侧群细胞(Side Population, SP)的亚群细胞,随后发现存在于各种非造血组织 [37] 。这些细胞的特征是可外排活性染料Hoechst33342,与真正的干细胞有许多相同的特征。SP细胞有助于肝实质的再生或骨骼肌管的形成。甲状腺中也发现SP细胞 [38] ;小鼠中,SP细胞大部分位于滤泡间隙中,少于甲状腺总细胞的1%。SP细胞表达干细胞标志物Oct-4和核干因子(Nucleostemin),而几乎检测不到分化标志物如甲状腺球蛋白(Tg)和甲状腺过氧化物酶(TPO)。此外,只有很少的SP细胞表达C细胞标志物——降钙素。人类结节性甲状腺肿的甲状腺细胞中已分离出SP细胞,并显示与小鼠SP细胞相似的分子特征 [39] 。通常,培养中的SP细胞会进行组织特异性分化。值得注意的是,从正常小鼠甲状腺分离的SP细胞在培养中保持未分化状态,并且不能排列成卵泡样结构。相反,人类SP细胞能够在体内增殖,具有甲状腺表型,对TSH应答。小鼠和人类SP细胞分别来源于正常和甲状腺肿组织,尚不清楚小鼠和人类SP细胞之间的差异是否取决于培养条件不同或细胞来源不同。

除了SP细胞,实性细胞巢(Solid Cell Nests, SCN)的主要细胞也显示许多干细胞的特征。在这些细胞中,不表达生成甲状腺球蛋白或降钙素的基因特异性,而表达端粒酶 [40] 和p63 [41] , p63是常在多层上皮细胞的基底/干细胞中检测到的转录因子。此外,SCN的主要细胞中BCL2的表达增加 [40] ,BCL2是在TFCs中持续表达的抗凋亡蛋白 [42] 。这种分子特征与干细胞的定义相符,提示SCN的主要细胞可能是分化为产生激素细胞的多能干细胞的来源。

人类TFCs更新缓慢,一生约分裂5次 [36] 。因此,人在出生后甲状腺表现为“休眠器官”。然而在动物模型中已经证明,甲状腺在受到严重干扰后(如严重的实验性甲状腺炎 [43] 或甲状腺部分切除术 [44] )可再生和恢复滤泡结构。甲状腺部分切除术后,表达Sca 1(干细胞抗原1)的细胞在术后的几天内增殖 [45] ,该细胞位于甲状腺的非滤泡间质区。

以前的数据似乎表明,甲状腺的再生可能是甲状腺干/祖细胞替换被破坏的滤泡细胞池而增殖和分化的结果。然而,我们目前缺乏甲状腺干细胞存在的确凿证据,不知道这些细胞的生理学和病理学作用。

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