Sonic hedgehog regulates early human thymocyte differentiation by counteracting the IL-7-induced development of CD34+ precursor cells
Sonic hedgehog regulates early human thymocyte differentiation by counteracting the IL-7-induced development of CD34+ precursor cells
复制标题
DOI：
10.4049/jimmunol.173.8.5046
复制
发表时间：
2004-10-15
影响因子：
4.4
通讯作者：
Vicente, A
中科院分区：
文献类型：
--
作者：
Gutiérrez-Frías, C;Sacedon, R;Vicente, A
Hedgehog (Hh) 信号分子家族通常通过调节细胞分化和增殖在多种组织的发育中发挥作用。最近的结果表明，Hh 信号通路的不同成分在人类胸腺中表达。在这项研究中，我们研究了 Sonic Hedgehog (Shh) 在人胸腺内 T 细胞成熟中的潜在作用。结果表明，Hh 受体的两种成分（Patched 和 Smoothened）的表达主要局限于正在分化为 T 细胞谱系的 CD34(+) 前体细胞。 Shh 显着增加调节 bcl-2 和 bax 蛋白表达的 CD34(+) T 细胞前体的活力，并抑制其增殖。用Shh处理嵌合人-小鼠胎儿胸腺器官培养物导致胸腺细胞分化停滞和CD34+祖细胞积累。这种作用主要归因于Shh能够抵抗IL-7诱导的CD34(+)细胞的增殖和分化。 Shh 下调前体细胞群中 IL-7R 以及基质衍生因子 1 趋化因子受体 CXCR4 的表达，并抑制 IL-7 依赖性 STAT5 磷酸化。因此，Shh可能作为胸腺内CD34(+)前体细胞的维持因子。
The Hedgehog (Hh) family of signaling molecules normally functions in the development of numerous tissues by regulating cellular differentiation and proliferation. Recent results have demonstrated that the different components of the Hh signaling pathway are expressed in the human thymus. In this study, we investigate the potential role of Sonic hedgehog (Shh) in human intrathymic T cell maturation. Results show that the expression of the two components of the Hh receptor, Patched and Smoothened, is mostly restricted to CD34(+) precursor cells that are committing to the T cell lineage. Shh significantly increased the viability of CD34(+) T cell precursors modulating bcl-2 and bax protein expression, and also inhibited their proliferation. The treatment of chimeric human-mouse fetal thymus organ cultures with Shh resulted in an arrested thymocyte differentiation and an accumulation of CD34+ progenitor cells. This effect was mainly attributed to the ability of Shh to counteract the IL-7-induced proliferation and differentiation of CD34(+) cells. Shh down-regulated in the precursor cell population the expression of IL-7R as well as stromal-derived factor-1 chemokine receptor, CXCR4, and inhibited IL-7-dependent STAT5 phosphorylation. Therefore, Shh may function as a maintenance factor for intrathymic CD34(+) precursor cells.