Abstract: Lupus nephritis (LN) is a prevalent and life-threatening manifestation, affecting 30-60% systemic lupus erythematosus (SLE) patients worldwide. Pathogenesis of LN remains elusive and patients often present poor treatment responses, urging for a need in understanding LN progression for therapeutics development. Previous studies in SLE mouse models have indicated the pathogenic roles of macrophages in LN, yet the translational potential of these findings was limited as mice fail to recapitulate genetic heterogeneity in human. To overcome this hurdle, we have generated an LN model from patient-derived expanded potential pluripotent stem cells (EPSCs) for mechanistic study. Specifically, peripheral blood mononuclear cells (PBMCs) from healthy individuals and SLE patients were reprogrammed into EPSCs, then differentiated into macrophages and kidney organoids for phenotypic and functional characterization. Irrespective of disease status, EPSC-derived macrophages were phenotypically and functionally comparable to PBMC-derived macrophages in terms of the ability to phagocytose apoptotic cells and releasing inflammatory cytokines upon bacterial ligand stimulation. In addition, all EPSCs followed a concordant differentiation trajectory into kidney organoids, suggesting that there is unlikely any kidney developmental defect in SLE patients. To mimic SLE-like microenvironment, macrophages or kidney organoids were exposed to various pathogenic factors for characterization. Transcriptomic analysis revealed unique enrichment in genes related to protein translation and cell activation in patient EPSC-macrophages upon exposure to SLE patient serum. On the other hand, enrichment of genes related to kidney diseases and fibrosis were noticed in immune complex (IC) stimulated kidney organoids. Further work will be done to delineate the interplay between kidney cells and macrophages in the presence of SLE pathogenic factors. Ultimately, this platform will be useful for drug screening to identify therapeutics specific for managing kidney inflammation in LN patients.
Funding Source: This project is funded by Health@InnoHK under Innovation and Technology Commission, Hong Kong.
