Multiomics profiling of mouse polycystic kidney disease progression at a single- cell resolution

• 成果类型: Article
• 署名作者: Muto, Yoshiharu; Yoshimura, Yasuhiro; Wu, Haojia; Panesso, Monica Chang -; Ledru, Nicolas; Woodward, Owen M.; Outeda, Patricia; Cheng, Tao; Mahjoub, Moe R.; Watnick, Terry J.; Humphreys, Benjamin D.
• 署名单位: Washington University (WUSTL); University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; Washington University (WUSTL); Washington University (WUSTL)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13004
• DOI: 10.1073/pnas.2410830121
• 发表日期: 2024-10-15
• 关键词: expression; protein-1

摘要

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single- nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late time- points, consisting of 125,434 single- nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell- type- specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single- nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single- cell resolution.