Kidney Hematopoietic Stem and Progenitor Cells Contribute to Myeloid Development and Pathology in Lupus Nephritis

Objectives The hematopoietic system maintains homeostasis by balancing myeloid and lymphoid cell production in the bone marrow (BM). In response to increased hematopoietic demand, extramedullary hematopoiesis (EMH) may occur in non-lymphoid organs. We investigated the role of EMH and kidney-resident hematopoietic stem and progenitor cells (HSPCs) in lupus nephritis (LN) pathogenesis. Methods Two murine LN models (MRL/lpr and TLR7 agonist-induced) were used to identify and characterize lineage-negative (Lin⁻) CD45⁺Sca1⁺ progenitor cells in the kidney. The association with disease severity was assessed using clinical parameters and histology. Single-cell RNA sequencing, including BM-to-kidney trajectory analysis and adoptive transfer experiments, evaluated lineage potential and pathogenicity. Stromal cell-derived hyaluronan (HA) was visualized by immunostaining. Urine samples from patients with LN were analyzed for hematopoietic progenitors and HA levels. Results Kidney Lin⁻CD45⁺Sca1⁺ cells were enriched in LN mice and correlated with increased proteinuria, elevated blood urea nitrogen, and kidney histological severity. These cells demonstrated a myeloid differentiation potential and shared transcriptional features with BM progenitors. Trajectory analysis indicated that BM-derived progenitors migrate to the kidneys and undergo local maturation. Adoptive transfer of LN-derived BM HSPCs induced kidney damage and myeloid infiltration, particularly under TLR7 stimulation. Kidney Sca1⁺ cells expressed CD44 and localized near HA-producing stromal cells in the renal pelvis. In human LN, urinary progenitor cells correlated with kidney dysfunction and HA levels. Conclusions EMH occurs in the kidneys during LN and contributes to disease progression through local myeloid cell expansion. Targeting kidney progenitors may offer novel therapeutic strategies to control local inflammation in LN.