Synergistic, Context-Dependent, and Hierarchical Functions of Epithelial Components in Thymic Microenvironments
Synergistic, Context-Dependent, and Hierarchical Functions of Epithelial Components in Thymic Microenvironments
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DOI：
10.1016/j.cell.2012.01.049
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发表时间：
2012-03-30
期刊：
影响因子：
64.5
通讯作者：
Boehm, Thomas
中科院分区：
文献类型：
--
作者：
Calderon, Lesly;Boehm, Thomas
专门的生态位环境指定和维持干细胞和祖细胞，但鲜为人知的是，在体内的身份和功能的相互作用的生态位组件。在这里，我们描述了一个模块化的系统，人工胸腺生成环境中的小鼠胚胎。缺乏造血功能但在生理上可接近造血祖细胞的胸腺上皮通过四种因子（趋化因子Ccl 25和Cxcl 12、细胞因子Scf和Notch配体DLL 4）的单独和组合表达而功能化。不同的表型和可变数量的造血细胞在所产生的上皮环境中揭示了协同效应，上下文依赖性，和层次的相互作用分子。决定造血特性的令人惊讶的简单规则使得能够在体内工程化人工环境，其有助于不同的骨髓或T或B淋巴谱系前体的存在;此外，合成环境有助于获得用于分析目的和未来治疗应用的生理祖细胞类型。
Specialized niche environments specify and maintain stem and progenitor cells, but little is known about the identities and functional interactions of niche components in vivo. Here, we describe a modular system for the generation of artificial thymopoietic environments in the mouse embryo. Thymic epithelium that lacks hematopoietic function but is physiologically accessible for hematopoietic progenitor cells is functionalized by individual and combinatorial expression of four factors, the chemokines Ccl25 and Cxcl12, the cytokine Scf, and the Notch ligand DLL4. The distinct phenotypes and variable numbers of hematopoietic cells in the resulting epithelial environments reveal synergistic, context-dependent, and hierarchical interactions among effector molecules. The surprisingly simple rules determining hematopoietic properties enable the in vivo engineering of artificial environments conducive to the presence of distinct myeloid or T or B lymphoid lineage precursors; moreover, synthetic environments facilitate the procurement of physiological progenitor cell types for analytical purposes and future therapeutic applications.