Origin and Differentiation Trajectories of Fibroblastic Reticular Cells in the Splenic White Pulp

The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here, definition of the embryonic origin and tracing of the differentiation trajectories of fibroblastic reticular cells (FRCs) was enabled by the establishment of FRC-specific fate-mapping in mice. We found that all reticular cell subsets descend from pluripotent progenitors that emerge at embryonic day 19.5 from Sca-1 periarterial progenitors. Commitment of FRC progenitors was 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. Finally, the lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveiled that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a pluripotent periarterial progenitor cell.