Deciphering Intercellular Communication of the Immune Landscape within Autosomal Dominant Polycystic Kidney Disease Microenvironment at Single-Cell Resolution.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that often leads to end-stage renal disease, with disease progression deeply influenced by the renal microenvironment. This study aims to unravel the critical cellular types and their intricate interactions within the ADPKD microenvironment.

Methods: Leveraging single-cell transcriptome data from seven ADPKD and three healthy human kidney samples, we systematically dissected the cellular landscape of the ADPKD microenvironment. Our approach included CellChat for cell-cell communication analysis, VISION for pathway enrichment analysis, pySCENIC for regulon activity calculation, and Monocle V3 for pseudotime trajectory construction.

Results: We identified nine major cell lineages, with a notable increase of mononuclear phagocytes (MNPs), T cells, and fibroblasts in the ADPKD microenvironment. These cells collectively orchestrated a distinctive microenvironment, marked by complex intercellular networks. Notably, a specific subset of macrophages exhibited an "M2-like" phenotype, which was driven by IL-10 signaling from M1-like macrophages and contributed to cyst cell proliferation. Immunosuppression was predominantly mediated by CD4+ T cells, activated by macrophages through immune checkpoint pathways, such as PDL1 signaling. The fibrotic expansion was a cumulative effect of fibroblast activation and proliferation, modulated by macrophages and cyst-lining epithelial cells.

Conclusion: This comprehensive investigation provides valuable insights into the diverse landscapes of the ADPKD microenvironment at single-cell resolution, emphasizing MNPs, T cells, and fibroblasts. The study unveils complex interactions among these cell types, shedding light on an understanding of the immunological aspect of ADPKD and proposing potential therapeutic targets.