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Decoding myofibroblast origins in human kidney fibrosis
Open accessAbstract
Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist 1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood 1,2,4. 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.
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“Recent studies have implicated a range of mesenchymal progenitor cells (MPs) in the initiation and propagation of fibrosis28–30.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [30]
Experimental — accuracy not yet measuredIn the citing paper
“For example, fatty acids amplify the inflammatory response by interacting with transcription factors such as HNF4α and TLRs.155,156”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [156]
In the citing paper
“Fibroblasts, in addition to displaying significant functional heterogeneity, are capable of remarkable degrees of plasticity and phenotype switching during progression and regression of fibrosis30,35,36.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [30]
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Sorted by citations
Fibrosis: from mechanisms to medicines
Henderson, N. C., Rieder, F., & Wynn, T. A. (2020) · Nature · doi:10.1038/s41586-020-2938-9 · Cited by 1,868
Self-citationFibroblasts: Origins, definitions, and functions in health and disease
Plikus, M. V., Wang, X., Sinha, S., Forte, E., Thompson, S. M., Herzog, E. L., Driskell, R. R., Rosenthal, N. A., Biernaskie, J. A., & Horsley, V. (2021) · Cell · doi:10.1016/j.cell.2021.06.024 · Cited by 1,247
Kidney fibrosis: from mechanisms to therapeutic medicines
Huang, R., Fu, P., & Ma, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01379-7 · Cited by 876
Spatial multi-omic map of human myocardial infarction
Kuppe, C., Ramirez Flores, R. O., Li, Z., Hayat, S., Levinson, R. T., Liao, X., Hannani, M. T., Tanevski, J., Wünnemann, F., Nagai, J. S., et al. (2022) · Nature · doi:10.1038/s41586-022-05060-x · Cited by 772
Self-citationAn atlas of healthy and injured cell states and niches in the human kidney
Lake, B. B., Menon, R., Winfree, S., Hu, Q., Ferreira, R. M., Kalhor, K., Barwinska, D., Otto, E. A., Ferkowicz, M. J., Diep, D. H., et al. (2023) · Nature · doi:10.1038/s41586-023-05769-3 · Cited by 784
Metadata
- Authors
- Kuppe, C., Ibrahim, M. M., Kranz, J., Zhang, X., Ziegler, S., Perales-Patón, J., Jansen, J., Reimer, K. C., Smith, J. R., Dobie, R., Wilson-Kanamori, J. R., Halder, M., Xu, Y., Kabgani, N., Kaesler, N., Klaus, M., Gernhold, L., Puelles, V. G., Huber, T. B., Boor, P., Menzel, S., Hoogenboezem, R. M., Bindels, E. M. J., Steffens, J., Floege, J., Schneider, R. K., Saez-Rodriguez, J., Henderson, N. C., & Kramann, R.
- Affiliations
- RWTH Aachen University (DE)
- Sankt-Antonius-Hospital Eschweiler (DE)
- Heidelberg University (DE)
- Radboud University Nijmegen (NL)
- Centre for Inflammation Research (GB)
- University Medical Center Hamburg-Eppendorf (DE)
- Erasmus MC Cancer Institute (NL)
- Erasmus MC (NL)
- Corresponding author
- Kramann, Rafael
- ORCID
- Kuppe, Christoph
- Ibrahim, Mahmoud M.
- Kranz, Jennifer
- Zhang, Xiaoting
- Ziegler, Susanne
- Perales-Patón, Javier
- Jansen, Jitske
- Reimer, Katharina C.
- Smith, James R.
- Dobie, Ross
- Wilson-Kanamori, John R.
- Halder, Maurice
- Kaesler, Nadine
- Klaus, Martin
- Puelles, Victor G.
- Huber, Tobias B.
- Boor, Peter
- Hoogenboezem, Remco M.
- Bindels, Eric M. J.
- Floege, Jürgen
- Schneider, Rebekka K.
- Saez-Rodriguez, Julio
- Henderson, Neil C.
- Kramann, Rafael
- Venue
- Nature
- Published
- 2020-11-11
- Volume
- 589
- Issue
- 7841
- Pages
- 281-286
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7611626
- OpenAlex
- W3104014715
- Cited by
- 769
- References
- 86
- Citations by year
- 2026: 147 · 2025: 128 · 2024: 148 · 2023: 139 · 2022: 115 · 2021: 87 · 2020: 3
- FWCI
- 54.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- Funders
- European Hematology Association
- Wellcome Trust (219542/Z/19/Z, 104366/Z/14/Z)
- British Heart Foundation (RM/17/3/33381, RE/18/5/34216)
- Deutsche Forschungsgemeinschaft (TRR57, SFBTRR219, BO3755/3‐1, TRR219, CRC 1192, SFB‐TRR57, SCHN 1188/5-1, BO3755/6-1, CRU344)
- Bundesministerium für Bildung und Forschung (01GM1901A, STOP‐FSGS 01GM1901A)
- Else Kröner-Fresenius-Stiftung
- RWTH Aachen University (SFBTRR219, O3-11)
- Medical Research Council
- H2020 European Research Council (677448)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- renal fibrosis, myofibroblast origin, chronic kidney disease, pericytes, fibroblasts, proximal tubule, NKD2, cell fate tracing, single-cell transcriptomics, spatial transcriptomics, ATAC-seq
- MeSH terms
- RNA-Seq, Animals, Calcium-Binding Proteins, Cell Differentiation, Extracellular Matrix, Female, Fibroblasts, Fibrosis, Humans, Kidney Tubules, Male, Mesoderm, Case-Control Studies, Cell Lineage, Pericytes, Receptor, Platelet-Derived Growth Factor alpha, Receptor, Platelet-Derived Growth Factor beta, Adaptor Proteins, Signal Transducing, Mice, Renal Insufficiency, Chronic, Myofibroblasts, Single-Cell Analysis, Transcriptome
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