Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors
Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors
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DOI：
10.1182/blood-2011-04-350553
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发表时间：
2011-11-10
期刊：
影响因子：
20.3
通讯作者：
Perreault, Claude
中科院分区：
文献类型：
--
作者：
Heinonen, Krista M.;Vanegas, Juan Ruiz;Perreault, Claude
胸腺萎缩是人类最常见的免疫病理学，它的发生是由几个因素加速的，这些因素在接受化疗的患者中合并，最重要的是在造血细胞移植的接受者中。我们以前已经表明，造血细胞移植后的胸腺功能改善逆转录病毒过表达Wnt 4在供体造血细胞。在这里，通过使用传统的和条件无效突变小鼠，我们表明，Wnt 4调节稳态胸腺细胞的胸腺上皮细胞（TEC）依赖性机制。Wnt 4的缺乏抑制了胎儿和出生后胸腺的扩张，导致TEC数量减少，髓质与皮质TEC比例改变，以及最不成熟的cKit（hi）胸腺细胞前体的不成比例的损失。Wnt 4也与维持成年胸腺生成有关，尽管一旦胸腺退化开始，其缺失的影响更为微妙。总之，我们的研究结果表明，Wnt 4通过调节TEC扩张和最早的TEC依赖性步骤的胸腺细胞发育在胎儿和出生后的胸腺控制胸腺的大小。因此，Wnt 4及其下游信号通路可能是改善胸腺萎缩受试者胸腺输出的有趣候选者。（血。2011;118（19）：5163-5173）
Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit(hi) thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19):5163-5173)