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Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis
Eoin D. O’Sullivan, … , Hassan Dihazi, David A. Ferenbach
Eoin D. O’Sullivan, … , Hassan Dihazi, David A. Ferenbach
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e154124. https://doi.org/10.1172/jci.insight.154124.
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Research Article Cell biology Nephrology

Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis

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Abstract

Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-β–mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies.

Authors

Eoin D. O’Sullivan, Katie J. Mylonas, Rachel Bell, Cyril Carvalho, David P. Baird, Carolynn Cairns, Kevin M. Gallagher, Ross Campbell, Marie Docherty, Alexander Laird, Neil C. Henderson, Tamir Chandra, Kristina Kirschner, Bryan Conway, Gry H. Dihazi, Michael Zeisberg, Jeremy Hughes, Laura Denby, Hassan Dihazi, David A. Ferenbach

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Figure 5

Senescent cells persist following renal injury with subsequent maladaptive repair.

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Senescent cells persist following renal injury with subsequent maladapti...
(A) Schematic of human kidney sample retrieval (n = 22). (B) Human kidney fibrosis. Red staining indicates Picrosirius red staining of collagen networks. * denotes significance at P < 0.05. Uninjured 3.3% (s.d. 3.3) versus obstruction 18.6% (s.d. 6.1) versus after obstruction 14% (s.d. 4.5), ANOVA, uninjured versus obstructed, P = 0.002 CI 7.4–23.3, uninjured versus after obstruction P = 0.002 CI 3.9–18.7, obstruction versus after obstruction P = 0.6 CI –10.14–2.11. For all box plots, the center line represents the mean, the box limits the first and third quartiles, and the whiskers are ± 1.5 × IQR. Scale bar = 50 μm. (C) Human kidney senescence. P21CIP1 staining demonstrating senescent epithelial cells. Arrows point to P21CIP1+ nuclei. Y axis shows fold change of senescent tubules per kidney relative to the mean number of senescent tubules in the uninjured control group. Uninjured 0.9 (s.d. 0.9) versus obstruction 10.5 (s.d. 11.4) versus after obstruction 7.8 (s.d. 4.3), Kruskal-Wallis rank sum test, uninjured versus obstructed, P = 0.009 CI 1.5–29.6, uninjured versus after obstruction P = 0.001 CI 2.7–12.5, obstruction versus after obstruction P = 0.2 CI: –5.5–14.5.

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