DKK1 介导的 Wnt 信号通路抑制导致出生后小鼠的 TEC 祖细胞缺失和胸腺退化。

BACKGROUND: Thymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+) Foxn1(+) and Aire(+) TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments. CONCLUSIONS/SIGNIFICANCE: Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated with cancer therapy and bone marrow transplants.

背景：胸腺上皮细胞 (TEC) 微环境对于从骨髓中招募 T 细胞前体以及随后扩增和选择胸腺细胞以产生成熟的自身耐受 T 细胞库至关重要。控制这些关键微环境的初始发育和随后维持的分子机制尚未明确。Wnt 信号已被证明对几种上皮组织和器官的发育很重要。Wnt 信号的调节也已被证明对早期胸腺细胞和胸腺上皮细胞的发育都有影响。然而，由于胸腺器官发生的早期阻断或小鼠的死亡，使得无法分析经典 Wnt 信号在维持出生后胸腺 TEC 中的作用。

方法/主要发现：在这里，我们证明在成年小鼠的皮质和髓质中，TEC 中经典 Wnt 抑制剂 DKK1 的四环素调控表达会导致胸腺迅速退化，特征是 DeltaNP63(+)Foxn1(+) 和 Aire(+)TEC 的丧失、K5K8DP TEC 的丧失，这些 TEC 被认为代表或包含不成熟的 TEC 祖细胞、TEC 增殖减少以及囊性结构的发育，类似于衰老的胸腺。从 DKK1 涉及的小鼠中去除 DKK1 会导致完全恢复，表明经典 Wnt 信号对于分化或增殖 TEC 群体是必需的，这些群体需要维持适当组织的成年胸腺上皮细胞微环境。

结论/意义：总的来说，这项研究的结果表明，TEC 中的经典 Wnt 信号对于维持出生后胸腺的上皮微环境是必需的，可能是通过对 TEC 祖细胞/干细胞群体的影响。Wnt 信号的下游靶标，负责维持这些 TEC 祖细胞，可能为对抗与年龄相关的胸腺萎缩或与癌症治疗和骨髓移植相关的过早胸腺退化的治疗提供有用的靶点。