Popa Ileana, Zubkova Iryna, Medvedovic Mario, Romantseva Tatiana, Mostowski Howard, Boyd Richard, Zaitseva Marina
Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, USA.
Int Immunol. 2007 Nov;19(11):1249-60. doi: 10.1093/intimm/dxm092. Epub 2007 Sep 6.
Studies of HIV-1-infected individuals on anti-retroviral therapies and of patients receiving lymphoablating treatments indicate that the thymus retains restorative capacity even in adults. The contributions of the thymic epithelial cells (TECs) to the regeneration of the thymus and the identity of epithelial cell progenitors were evaluated in murine models of transient thymic atrophy followed by a complete regeneration. Using microarray approach, we analyzed the pattern of gene expression in TECs sorted from mice that were depleted of thymocytes by steroid treatment or by irradiation. The initial analysis identified significant increases in the mRNA for cMyc, Trp63 and Tcf3 transcription factors known to be expressed in early epithelial cell progenitors in tissues other than the thymus. Immunohistochemistry showed that in involuted thymuses, the cMyc and Trp63 proteins were expressed in a subset of cortical thymic epithelial cells (cTECs) that were keratin 5 positive (K5(+)), typifying cTEC precursors. Importantly, confocal microscopy established that epithelial cells with the phenotype of putative TEC progenitors (i.e. K5(+)K8(+)) expressed the Trp63 protein and confirmed that K5(+)K8(+) TEC progenitors expanded significantly during atrophy and prior to the thymic regeneration. Thus, our data demonstrated for the first time that critical steps in the recovery of the adult thymus include expansion of TEC progenitors and elevated expression of Trp63, cMyc and Tcf3 transcription factors in the thymic stroma. These results suggest that TEC progenitors could be reactivated in the adult thymus and, therefore, reactivation of TEC progenitors could provide a new approach for thymic reconstitution.
对接受抗逆转录病毒疗法的HIV-1感染者以及接受淋巴细胞清除治疗的患者的研究表明，即使在成年人中，胸腺仍保留恢复能力。在短暂性胸腺萎缩后完全再生的小鼠模型中，评估了胸腺上皮细胞（TEC）对胸腺再生的贡献以及上皮细胞祖细胞的特性。使用微阵列方法，我们分析了通过类固醇治疗或照射清除胸腺细胞的小鼠中分离出的TEC的基因表达模式。初步分析发现，cMyc、Trp63和Tcf3转录因子的mRNA显著增加，这些转录因子已知在胸腺以外的组织中的早期上皮细胞祖细胞中表达。免疫组织化学显示，在萎缩的胸腺中，cMyc和Trp63蛋白在皮质胸腺上皮细胞（cTEC）的一个亚群中表达，这些细胞角蛋白5呈阳性（K5(+)），代表cTEC前体。重要的是，共聚焦显微镜证实，具有假定TEC祖细胞表型的上皮细胞（即K5(+)K8(+)）表达Trp63蛋白，并证实K5(+)K8(+) TEC祖细胞在萎缩期间和胸腺再生之前显著扩增。因此，我们的数据首次证明，成年胸腺恢复的关键步骤包括TEC祖细胞的扩增以及胸腺基质中Trp63、cMyc和Tcf3转录因子表达的升高。这些结果表明，TEC祖细胞可以在成年胸腺中重新激活，因此，TEC祖细胞的重新激活可能为胸腺重建提供一种新方法。
