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Nat Commun. 2019 Apr 15;10(1):1739. doi: 10.1038/s41467-019-09728-3.

Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp.

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Institute of Immunobiology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.
Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich, 8057, Zurich, Switzerland.
Division of Stem Cell Regulation Research, Osaka University Medical School, 565-0871, Osaka, Japan.
Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225, Düsseldorf, Germany.
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
Institute of Immunology, Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, 93053, Regensburg, Germany.
Institute of Immunobiology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.


The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here we establish fibroblastic reticular cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all reticular cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular reticular cells function both as adult lymphoid organizer cells and mural cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a multipotent periarterial progenitor cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of reticular cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.

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