Decoding myofibroblast origins in human kidney fibrosis.
1. Nature. 2021 Jan;589(7841):281-286. doi: 10.1038/s41586-020-2941-1. Epub 2020 Nov 11. Decoding myofibroblast origins in human kidney fibrosis. Kuppe C(#)(1)(2), Ibrahim MM(#)(1)(2)(3), Kranz J(2)(4)(5), Zhang X(2), Ziegler S(2), Perales-Patón J(2)(6)(7), Jansen J(2)(8)(9), Reimer KC(1)(2)(10), Smith JR(11), Dobie R(11), Wilson-Kanamori JR(11), Halder M(1)(2), Xu Y(2), Kabgani N(2), Kaesler N(1)(2), Klaus M(12), Gernhold L(12), Puelles VG(12)(13), Huber TB(12), Boor P(1)(14), Menzel S(2), Hoogenboezem RM(15), Bindels EMJ(15), Steffens J(4), Floege J(1), Schneider RK(10)(15), Saez-Rodriguez J(6)(7)(16), Henderson NC(11)(17), Kramann R(18)(19)(20). Author information: (1)Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany. (2)Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany. (3)Bayer Pharma AG, Berlin, Germany. (4)Department of Urology and Paediatric Urology, St Antonius Hospital, Eschweiler, Germany. (5)Department of Urology, Kidney Transplantation Centre, Martin-Luther-University, Halle, Germany. (6)Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, BioQuant, Heidelberg, Germany. (7)Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany. (8)Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. (9)Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands. (10)Department of Cell Biology, Institute for Biomedical Technologies, RWTH Aachen University, Aachen, Germany. (11)Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. (12)III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (13)Department of Anatomy and Developmental Biology, Monash Biomedical Discovery Institute, Monash University, Melbourne, Victoria, Australia. (14)Department of Pathology, RWTH Aachen University, Aachen, Germany. (15)Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. (16)Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg University, Heidelberg, Germany. (17)MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. (18)Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany. rkramann@gmx.net. (19)Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany. rkramann@gmx.net. (20)Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands. rkramann@gmx.net. (#)Contributed equally Comment in Nat Rev Nephrol. 2021 Mar;17(3):151. doi: 10.1038/s41581-020-00382-3. Kidney Int. 2021 Jun;99(6):1259-1261. doi: 10.1016/j.kint.2021.02.016. J Urol. 2021 Aug;206(2):480-482. doi: 10.1097/JU.0000000000001849. Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis. DOI: 10.1038/s41586-020-2941-1 PMCID: PMC7611626 PMID: 33176333 [Indexed for MEDLINE] Conflict of interest statement: Competing interest The authors have no competing interests.