Osr1-expressing mesoderm contributes to lymphatic vessel assembly and complexity in the mammalian kidney.

Lymphatic vessels perform diverse functions, ranging from fluid homeostasis to immune regulation, and arise from multiple cellular origins to form organ-specific networks. Despite their importance in kidney disease and transplant immunity, the origins of kidney lymphatics are unknown. Using genetic lineage tracing in mice, we identify two origins of kidney lymphatics. Most kidney lymphatics arise from a Tie2+ endothelial origin shared by other organs. However, Osr1+ mesoderm generates approximately 15% of kidney lymphatics, without contributing to heart, mesentery, and skin lymphatics. Interrogating single-cell transcriptomics data of mice and humans reveals lymphatic progenitors within Osr1+ mesoderm. Lymphatic clusters forming by de novo assembly originate from both Osr1+ and Tie2+ lineages. Deleting the lymphatic specification gene Prox1 in Osr1+ mesoderm reduces lymphatic cluster number, impairing overall lymphatic network complexity, with lower glomerular number. Thus, an Osr1+ mesodermal origin contributes to organ-specific lymphatic assembly, with consequences for kidney health, disease, and regeneration.