Fate mapping and scRNA sequencing reveal origin and diversity of lymph node stromal precursors

• Published in: Immunity (Cambridge, Mass.) Vol. 55; no. 4; pp. 606 - 622.e6
• Main Authors: Lenti, Elisa, Genovese, Luca, Bianchessi, Silvia, Maurizio, Aurora, Sain, Simona Baghai, di Lillo, Alessia, Mattavelli, Greta, Harel, Itamar, Bernassola, Francesca, Hehlgans, Thomas, Pfeffer, Klaus, Crosti, Mariacristina, Abrignani, Sergio, Evans, Sylvia M., Sitia, Giovanni, Guimarães-Camboa, Nuno, Russo, Vincenzo, van de Pavert, Serge A., Garcia-Manteiga, Jose Manuel, Brendolan, Andrea
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-04-2022; Elsevier
• Subjects: Endothelial Cells - metabolism; fibroblastic reticular cell; follicular dendritic cell; Life Sciences; lineage tracing; lymph node development; Lymph Nodes; marginal reticular cell; perivascular cell; Sequence Analysis, RNA; single cell RNA-seq; Single-Cell Analysis; Stromal Cells; Transcription Factors - metabolism; single cell RNA-seq; marginal reticular cell; lymph node development; lineage tracing; follicular dendritic cell; perivascular cell; fibroblastic reticular cell
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2022.03.002

Lymph node (LN) stromal cells play a crucial role in LN development and in supporting adaptive immune responses. However, their origin, differentiation pathways, and transcriptional programs are still elusive. Here, we used lineage-tracing approaches and single-cell transcriptome analyses to determine origin, transcriptional profile, and composition of LN stromal and endothelial progenitors. Our results showed that all major stromal cell subsets and a large proportion of blood endothelial cells originate from embryonic Hoxb6+ progenitors of the lateral plate mesoderm (LPM), whereas lymphatic endothelial cells arise from Pax3+ progenitors of the paraxial mesoderm (PXM). Single-cell RNA sequencing revealed the existence of different Cd34+ and Cxcl13+ stromal cell subsets and showed that embryonic LNs contain proliferating progenitors possibly representing the amplifying populations for terminally differentiated cells. Taken together, our work identifies the earliest embryonic sources of LN stromal and endothelial cells and demonstrates that stromal diversity begins already during LN development.
[Display omitted]
•Progenitors of the LPM generate mature stromal cells in LNs•LN BECs and LECs have distinct mesodermal origin•Embryonic LN already contain different subsets of Cd34+ and Cxcl13+ cells•Stromal cell subsets across developmental stages maintain transcriptional similarities
LN stromal cells are crucial organizers of lymphoid compartments and regulators of adaptive immune responses, but their origin remains still elusive. Lenti et al. reveal that different stromal cell subsets originate from embryonic Hoxb6+ mesodermal progenitors and show that stromal diversity is acquired early during LN development.