biostudies-literatureUnknownMiller SJNIDDK NIH HHSNIAMS NIH HHSWellcome TrustNIH HHSPolycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as <i>PKD1</i> and <i>PKD2</i>, expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell and spatial transcriptomics atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Consistently across models, single cell RNA sequencing (scRNAseq) data revealed increased <i>Spp1</i> (osteopontin) expression and signaling from PKD-enriched clusters to Ly6c^lo monocytes. Global deletion of <i>Spp1</i> in <i>Pkd1</i> ^RC/RC mice resulted in reduced cyst severity, improved kidney function, and reduced Ly6c^lo monocyte numbers, suggesting that SPP1 signaling to Ly6c^lo monocytes promotes PKD progression. We also created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model specific changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.bioRxiv : the preprint server for biology2025.09.17.676846https://www.ebi.ac.uk/biostudies/studies/S-EPMC12458445biostudies-literatureA cross model spatial and single-cell atlas reveals the conserved involvement of osteopontin in polycystic kidney disease.PMC12458445R01 DK115752P30 AR048311K01 DK119375220895/Z/20/ZS10 OD028479R21 DK140693P30 DK079337314710/Z/24/ZR01 DK129255Do VLong DAMa QDarby IGAhmed KBStubbs JMiller SJDeVette CICowley BDHignite MPark YJafree DJGipson JRNusrat FWu WZimmerman CNCordova AMMaryam BZimmerman KAYoder BKLi XMa ALi ZLu SZhong HYashchenko AWeiser-Evans MSmith MEHopp KfalseA cross model spatial and single-cell atlas reveals the conserved involvement of osteopontin in polycystic kidney disease.Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as <i>PKD1</i> and <i>PKD2</i>, expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell and spatial transcriptomics atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Consistently across models, single cell RNA sequencing (scRNAseq) data revealed increased <i>Spp1</i> (osteopontin) expression and signaling from PKD-enriched clusters to Ly6c^lo monocytes. Global deletion of <i>Spp1</i> in <i>Pkd1</i> ^RC/RC mice resulted in reduced cyst severity, improved kidney function, and reduced Ly6c^lo monocyte numbers, suggesting that SPP1 signaling to Ly6c^lo monocytes promotes PKD progression. We also created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model specific changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.2025-01-01T00:00:00Z2025 Sep2026-05-04T03:17:58.741Z2026-05-04T03:13:22.304ZS-EPMC124584454100088810.1101/2025.09.17.676846