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Kidney Week

Abstract: PO1233

Exploring the Heterogeneity of Kidney Resident Macrophages Using Single-Cell RNA Sequencing

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Yashchenko, Alex, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Bland, Sarah Jane, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Li, Zhang, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Song, Cheng 'Jack', University of Southern California, Los Angeles, California, United States
  • Zimmerman, Kurt, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Background

Tissue resident macrophages are highly diverse, even when located within the same tissue. This diversity is thought to be driven by localization, ontological origin, time in tissue, and niche specific cues. Importantly, these underlying factors likely influence resident macrophage phenotype and function during disease initiation and progression.

Methods

To understand the diversity of kidney resident macrophages (KRM), we performed single cell RNA sequencing, parabiosis, and fate mapping on kidneys isolated from wild type and transgenic knock-in reporter mice.

Results

Using single cell RNA sequencing, we identified three subpopulations of KRM including one with enriched expression of Ccr2. Using Ccr2-RFP knock-in mice and Ms4a3cre Rosa Stopf/f TdT mice, we confirm that these resident macrophages were derived from monocyte precursors and preferentially localize to the renal cortex. Based on our single cell RNA sequencing data, we propose that monocytes undergo a series of differentiation steps upon entering the kidney in order to become Ccr2+ KRM. Analysis of single cell data using RNA Velocity and Monocle suggest that monocytes require Cx3cr1 in order to differentiate into Ccr2+ KRM. Loss of Cx3cr1 prevented the accumulation of Ccr2+ KRM and resulted in a skewed macrophage profile that prevented cilia mutant mice from developing severe cystic disease.

Conclusion

Collectively, our data indicate that monocytes undergo a series of differentiation steps upon entering the kidney and require Cx3cr1 for differentiation into pathogenic Ccr2+ KRM.

Funding

  • NIDDK Support