ORCID Profile
0000-0002-5551-6536
Current Organisation
Galecto Inc
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Publisher: American Society for Clinical Investigation
Date: 18-05-2020
DOI: 10.1172/JCI130834
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-05-2021
DOI: 10.1126/SCITRANSLMED.ABB0203
Abstract: The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor β1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.
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 Duncan Humphries.