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Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways
Open accessAbstract
The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.
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“two studies, focussing on populations of hypermethylated in cancer protein (Hic1)+Pdgfrα+ lymphocyte antigen 6 complex (LY6A)+ MP populations in heart and skeletal muscle, have elegantly demonstrated MP hierarchy, diversity in the pathophysiological roles of their progeny, and how fate determination of MP is context dependent31,32.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [31]
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“although Hic1 inactivation in skeletal muscle also resulted in a marked expansion of Pdgfrα+LY6A+ cells during homeostasis, this did not increase skeletal muscle fibrosis and had no substantial effect on skeletal muscle regeneration31”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [31]
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“Conditional genetic inactivation of Hic1 in mice led to activation and expansion of MPs in both heart and skeletal muscle, demonstrating that Hic1 is required for maintaining MP quiescence.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [31]
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Metadata
- Authors
- the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Der, E., Suryawanshi, H., Morozov, P., Kustagi, M., Goilav, B., Ranabothu, S., Izmirly, P., Clancy, R., Belmont, H. M., Koenigsberg, M., Mokrzycki, M., Rominieki, H., Graham, J. A., Rocca, J. P., Bornkamp, N., Jordan, N., Schulte, E., Wu, M., Pullman, J., Slowikowski, K., Raychaudhuri, S., Guthridge, J., James, J., Buyon, J., Tuschl, T., & Putterman, C.
- Affiliations
- Albert Einstein College of Medicine (US)
- Rockefeller University (US)
- Arkansas Children's Hospital (US)
- New York University (US)
- Montefiore Medical Center (US)
- Broad Institute (US)
- Oklahoma Medical Research Foundation (US)
- Corresponding author
- Buyon, Jill
- Tuschl, Thomas
- Putterman, Chaim
- ORCID
- Venue
- Nature Immunology
- Published
- 2019-05-20
- Volume
- 20
- Issue
- 7
- Pages
- 915-927
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6584054
- OpenAlex
- W2944872709
- Cited by
- 403
- References
- 52
- Citations by year
- 2026: 30 · 2025: 35 · 2024: 61 · 2023: 44 · 2022: 86 · 2021: 56 · 2020: 64 · 2019: 25
- FWCI
- 44.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-10-11)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR003167, UL1TR000371)
- National Human Genome Research Institute (U01HG009379, T32HG002295)
- National Institute of Allergy and Infectious Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (UH2AR067679, UH2AR067677, UH2AR067685, UH2AR067681, UH2AR067689, F31AR070582, UH2AR067676, UH2AR067694, UH2AR067691, UH2AR067690, UH2AR067688, UM2AR067678)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Rheumatology › Systemic Sclerosis and Related Diseases
- Keywords
- lupus nephritis, type I interferon response, renal tubular epithelial cells, keratinocytes, renal fibrosis, treatment non-response, skin biopsy, disease heterogeneity, membranous lupus nephritis, proliferative lupus nephritis, single-cell transcriptomics, personalized treatment
- MeSH terms
- Biopsy, Fibrosis, Humans, Interferon Type I, Kidney Tubules, Lupus Nephritis, Protein Binding, Skin, Signal Transduction, Keratinocytes, Extracellular Matrix Proteins, Cell Lineage, Computational Biology, Gene Expression Profiling, Single-Cell Analysis, Transcriptome
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