Session Information
Session Type: Poster Session C
Session Time: 10:30AM-12:30PM
Background/Purpose: Hematopoiesis primarily occurs in the bone marrow (BM), where hematopoietic stem and progenitor cells (HSPCs) originate. However, non-lymphoid tissues outside the BM can contribute to hematopoiesis through a process known as extramedullary hematopoiesis (EMH). Lupus nephritis (LN) is an autoimmune disease characterized by immune cell infiltration in the kidney. Although EMH in the kidney has been suggested, the origin and role of kidney HSPCs in LN remain unclear. We investigated whether kidney HSPCs contribute to LN pathogenesis using lupus-prone mouse models and urinary cells from patients with LN.
Methods: We examined medullary and extramedullary HSPCs in genetic (MRL/lpr) and chemically induced (TLR7 agonist) murine LN models. HSPCs were identified as CD45+ and Sca1+ within lineage (Lin; CD3, CD11b, CD45R/B220, Gr-1, and Ter119) negative cells. Kidney pathology was assessed through blood urea nitrogen (BUN), urine protein–creatinine ratio (UPCR), and histological scores. The hematopoietic potential was evaluated using a colony-forming unit (CFU) assay with sorted Lin–CD45+Sca1+ cells, and transcriptomic characteristics were analyzed using bulk RNA-sequencing (RNA-seq). Single-cell RNA-seq (scRNA-seq) was performed on whole BM and kidney from MRL/lpr or MRL/MPJ control mice to explore HSPCs migration and differentiation in LN. To examine the intrinsic pathogenic role of HSPCs, BM HSPCs from chemically induced LN (CD45.2) and vehicle-treated (CD45.1) mice were transferred to recipient (CD45.1/2) mice, with or without additional TLR7 agonist administration. Urinary cells from patients with LN (n=25) were assessed using flow cytometry.
Results: The proportion and absolute number of cells with HSPC phenotype (Lin–CD45+Sca1+) were significantly higher in the BM and kidneys of LN mice than in those of controls. The numbers of kidney HSPCs significantly correlated with kidney pathological parameters, including BUN and UPCR. The CFU assay showed that Lin–CD45+Sca1+ cells from kidneys of MRL/lpr mice showed hematopoietic potential, particularly forming CFU-Granulocyte–Macrophage (GM). Immune cell analysis within LN kidneys revealed significantly higher numbers of myeloid lineage cells than that in MRL/MPJ controls. Ly6Chi monocyte numbers correlated with kidney Lin–CD45+Sca1+ cell numbers. Bulk RNA-seq indicated that kidney and BM Lin–Sca1+ cells upregulated HSPC and myeloid lineage-related gene expression. The scRNA-seq revealed myeloid progenitors in the BM and kidney of MRL/lpr mice, showing tissue-specific developmental trajectories across overlapping subclusters. Adoptive transfer of TLR7-stimulated BM HSPCs led to significant immune cell infiltration and exacerbated pathologic severity. Myeloid-lineage cells were more abundant after the transfer of TLR7-treated BM HSPCs compared to vehicle-treated controls. In the urine of patients with LN, cells with HSPC phenotypes (Lin-CD45+CD34+CD38–CD10–CD45RA–CD90+) were identified, correlating significantly with LN severity.
Conclusion: Our findings suggested that dysregulated HSPCs in the kidney play a crucial role in LN pathogenesis through myeloid cell differentiation.
To cite this abstract in AMA style:
Yi H, Jung S, Cho M, Kim Y, Lee C, Yoo B, Lee J, Hong S. Kidney Hematopoietic Stem and Progenitor Cells Contribute to Immune Cell Development and Pathology in Lupus Nephritis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/kidney-hematopoietic-stem-and-progenitor-cells-contribute-to-immune-cell-development-and-pathology-in-lupus-nephritis/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/kidney-hematopoietic-stem-and-progenitor-cells-contribute-to-immune-cell-development-and-pathology-in-lupus-nephritis/