Synergistic, Context-Dependent, and Hierarchical Functions of Epithelial Components in Thymic Microenvironments

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.