Cheng J Song1, Zhang Li1, Ummey Khalecha Bintha Ahmed2, Sarah J Bland2, Alex Yashchenko2, Shanrun Liu3, Ernald J Aloria1, Jeremie M Lever4, Nancy M Gonzalez1, Marisa A Bickel5, Cory B Giles6,7, Constantin Georgescu6,7, Jonathan D Wren6,7, Mark L Lang8, Etty N Benveniste1, Laurie E Harrington1, Leo Tsiokas5, James F George9, Kenneth L Jones5, David K Crossman10, Anupam Agarwal4, Michal Mrug4,11, Bradley K Yoder1, Katharina Hopp12, Kurt A Zimmerman13,2. 1. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama. 2. Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 3. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama. 4. Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. 5. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 6. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma. 7. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 8. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 9. Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama. 10. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. 11. Department of Veterans Affairs Medical Center, Birmingham, Alabama. 12. Polycystic Kidney Disease Program, Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado Katharina.hopp@cuanschutz.edu kurt-zimmerman@ouhsc.edu. 13. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama Katharina.hopp@cuanschutz.edu kurt-zimmerman@ouhsc.edu.
Abstract
BACKGROUND: Inducible disruption of cilia-related genes in adult mice results in slowly progressive cystic disease, which can be greatly accelerated by renal injury. METHODS: To identify in an unbiased manner modifier cells that may be influencing the differential rate of cyst growth in injured versus non-injured cilia mutant kidneys at a time of similar cyst severity, we generated a single-cell atlas of cystic kidney disease. We conducted RNA-seq on 79,355 cells from control mice and adult-induced conditional Ift88 mice (hereafter referred to as cilia mutant mice) that were harvested approximately 7 months post-induction or 8 weeks post 30-minute unilateral ischemia reperfusion injury. RESULTS: Analyses of single-cell RNA-seq data of CD45+ immune cells revealed that adaptive immune cells differed more in cluster composition, cell proportion, and gene expression than cells of myeloid origin when comparing cystic models with one another and with non-cystic controls. Surprisingly, genetic deletion of adaptive immune cells significantly reduced injury-accelerated cystic disease but had no effect on cyst growth in non-injured cilia mutant mice, independent of the rate of cyst growth or underlying genetic mutation. Using NicheNet, we identified a list of candidate cell types and ligands that were enriched in injured cilia mutant mice compared with aged cilia mutant mice and non-cystic controls that may be responsible for the observed dependence on adaptive immune cells during injury-accelerated cystic disease. CONCLUSIONS: Collectively, these data highlight the diversity of immune cell involvement in cystic kidney disease.
BACKGROUND: Inducible disruption of cilia-related genes in adult mice results in slowly progressive cystic disease, which can be greatly accelerated by renal injury. METHODS: To identify in an unbiased manner modifier cells that may be influencing the differential rate of cyst growth in injured versus non-injured cilia mutant kidneys at a time of similar cyst severity, we generated a single-cell atlas of cystic kidney disease. We conducted RNA-seq on 79,355 cells from control mice and adult-induced conditional Ift88 mice (hereafter referred to as cilia mutant mice) that were harvested approximately 7 months post-induction or 8 weeks post 30-minute unilateral ischemia reperfusion injury. RESULTS: Analyses of single-cell RNA-seq data of CD45+ immune cells revealed that adaptive immune cells differed more in cluster composition, cell proportion, and gene expression than cells of myeloid origin when comparing cystic models with one another and with non-cystic controls. Surprisingly, genetic deletion of adaptive immune cells significantly reduced injury-accelerated cystic disease but had no effect on cyst growth in non-injured cilia mutant mice, independent of the rate of cyst growth or underlying genetic mutation. Using NicheNet, we identified a list of candidate cell types and ligands that were enriched in injured cilia mutant mice compared with aged cilia mutant mice and non-cystic controls that may be responsible for the observed dependence on adaptive immune cells during injury-accelerated cystic disease. CONCLUSIONS: Collectively, these data highlight the diversity of immune cell involvement in cystic kidney disease.
Authors: Z Su; X Wang; X Gao; Y Liu; C Pan; H Hu; R P Beyer; M Shi; J Zhou; J Zhang; A L Serra; R P Wüthrich; C Mei Journal: J Intern Med Date: 2014-03-02 Impact factor: 8.989
Authors: Jacqueline D Peda; Sally M Salah; Darren P Wallace; Patrick E Fields; Connor J Grantham; Timothy A Fields; Katherine I Swenson-Fields Journal: Dis Model Mech Date: 2016-08-04 Impact factor: 5.758
Authors: Bryan R Conway; Eoin D O'Sullivan; Carolynn Cairns; James O'Sullivan; Daniel J Simpson; Angela Salzano; Katie Connor; Peng Ding; Duncan Humphries; Kevin Stewart; Oliver Teenan; Riinu Pius; Neil C Henderson; Cécile Bénézech; Prakash Ramachandran; David Ferenbach; Jeremy Hughes; Tamir Chandra; Laura Denby Journal: J Am Soc Nephrol Date: 2020-09-25 Impact factor: 10.121