Single-Cell and CellChat Resolution Identifies Collecting Duct Cell Subsets and Their Communications with Adjacent Cells in PKD Kidneys

Abstract

ADPKD is a genetic disorder with a molecular complexity that remains poorly understood. In this study, we sampled renal cells to construct a comprehensive and spatiotemporally resolved gene expression atlas in whole Pkd1 mutant polycystic mouse kidneys at single-cell resolution. We characterized cell diversity and identified novel collecting duct (CD) cell subtypes in cystic kidneys. We further found that CD cells appear to take different cell fate trajectories, and the first and the most important step might take place around day 14 in Pkd1 homozygous kidneys. After that day, increased numbers of CD cells showed highly proliferative and fibrotic characteristics, as detected in later-stage Pkd1 homozygous kidneys, both of which should contribute to cyst growth and renal fibrosis. With a newly developed modeling algorithm, called CellChat Explorer, we identify cell-to-cell communication networks mediated by the ligand receptor, such as MIF-CD44/CD74, in cystic kidneys, and confirm them via the expression patterns of ligands and receptors in four major cell types, which addresses the key question as to whether and how Pkd1 mutant renal epithelial cells affect their neighboring cells. The allele-specific gene expression profiles show that the secretion of cytokines by Pkd1 mutant epithelial cells may affect the gene expression profiles in recipient cells via epigenetic mechanisms, and vice versa. This study can be used to drive precision therapeutic targeting of ADPKD.