ORCID Profile
0000-0003-1277-708X
Current Organisation
The University of Edinburgh
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Publisher: American Society for Clinical Investigation
Date: 22-11-2022
Publisher: Cold Spring Harbor Laboratory
Date: 15-05-2020
DOI: 10.1101/2020.05.14.095166
Abstract: The kidney has a limited capacity to repair following injury, however, the endogenous reparative pathways are not well understood. Here we employ integrated droplet- and plate-based scRNA-seq in the murine reversible unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single cell level during renal injury and resolution of fibrosis. We generate a comprehensive catalogue of the changes induced during injury and repair, revealing significant myeloid cell heterogeneity, which would not have been identifiable by conventional flow cytometry. We identify new markers for the myeloid populations within the kidney as well as identification of novel subsets including an Arg1 + monocyte population specific to early injury and a Mmp12 + macrophage subset exclusive to repair. Finally, using paired blood exchange to track circulating immune cells, we confirm that monocytes are recruited to the kidney early after injury and are the source of Ccr2 + macrophages that accumulate in late injury. Our data demonstrate the utility of complementary technologies to identify novel myeloid subtypes that may represent therapeutic targets to inhibit progression or promote regression of kidney disease.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-05-2023
DOI: 10.1126/SCITRANSLMED.ABN0736
Abstract: Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1 + ) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 + cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 + cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell–resolution transcriptomic analysis, we identified an “inflammatory” proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)–induced IHH production in vivo. TNF-induced Ubiquitin D ( Ubd ) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1 + cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8 -expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1 + cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-09-2020
Abstract: The innate immune system is central to injury and repair in the kidney, but the heterogeneity of myeloid cell subsets behind these processes is unknown. Complementary technologies—including bulk tissue transcriptomics, integrated droplet– and plate-based single-cell RNA sequencing, and paired blood exchange—resolved myeloid cell heterogeneity in a murine model of reversible unilateral ureteric obstruction, creating a single-cell atlas. The identified novel myeloid subsets could be targeted to ameliorate injury or enhance repair, including an Arg1+ monocyte subset present during injury and Mmp12+ macrophages present during repair. Standard flow cytometry to detect cell surface markers would have missed these subsets. Complementary techniques capture the complexity and dynamics of monocyte, dendritic cell, and macrophage phenotypes in the injured and repairing kidney. Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease. Integrated droplet– and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney. A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1 , before transitioning to become Ccr2 + macrophages that accumulate in late injury. Conversely, a novel Mmp12 + macrophage subset acts during repair. Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Laura Denby.