Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Clinical Sciences, Anatomy and Physiology Division, Faculty of Veterinary Medicine, Utrecht University, 3584 Utrecht, The Netherlands.
Cells. 2022 Aug 28;11(17):2679. doi: 10.3390/cells11172679.
The development of T lymphocytes in the thymus and their stem cell precursors in the bone marrow is controlled by Wnt signaling in strictly regulated, cell-type specific dosages. In this study, we investigated levels of canonical Wnt signaling during hematopoiesis and T cell development within the Axin2-mTurquoise2 reporter. We demonstrate active Wnt signaling in hematopoietic stem cells (HSCs) and early thymocytes, but also in more mature thymic subsets and peripheral T lymphocytes. Thymic epithelial cells displayed particularly high Wnt signaling, suggesting an interesting crosstalk between thymocytes and thymic epithelial cells (TECs). Additionally, reporter mice allowed us to investigate the loss of Axin2 function, demonstrating decreased HSC repopulation upon transplantation and the partial arrest of early thymocyte development in Axin2 full mutant mice. Mechanistically, loss of leads to supraphysiological Wnt levels that disrupt HSC differentiation and thymocyte development.
T 淋巴细胞在胸腺中的发育及其在骨髓中的干细胞前体的发育受 Wnt 信号的严格调控,具有严格的细胞类型特异性剂量依赖性。在这项研究中,我们利用 Axin2-mTurquoise2 报告基因研究了造血过程中和 T 细胞发育过程中经典 Wnt 信号的水平。我们发现在造血干细胞(HSCs)和早期胸腺细胞中存在活跃的 Wnt 信号,而且在更成熟的胸腺细胞亚群和外周 T 淋巴细胞中也存在活跃的 Wnt 信号。胸腺上皮细胞显示出特别高的 Wnt 信号,提示胸腺细胞和胸腺上皮细胞(TECs)之间存在有趣的串扰。此外,报告基因小鼠还允许我们研究 Axin2 功能的缺失,证明在移植后 HSC 的再定植减少,以及 Axin2 完全突变小鼠中早期胸腺细胞发育部分停滞。从机制上讲,Axin2 的缺失导致超生理水平的 Wnt 水平,破坏 HSC 的分化和胸腺细胞的发育。