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Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis
Xiaolin He, … , Jeffrey L. Wrana, Darren A. Yuen
Xiaolin He, … , Jeffrey L. Wrana, Darren A. Yuen
Published February 22, 2022
Citation Information: JCI Insight. 2022;7(4):e146243. https://doi.org/10.1172/jci.insight.146243.
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Research Article Nephrology Pulmonology

Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis

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Abstract

Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues. Despite this growing recognition, a number of important questions remain unanswered, including which cell types require YAP/TAZ activation for fibrosis to occur and the time course of this activation. Here, we present a detailed analysis of the role that myofibroblast YAP and TAZ play in organ fibrosis and the kinetics of their activation. Using analyses of cells, as well as multiple murine and human tissues, we demonstrated that myofibroblast YAP and TAZ were activated early after organ injury and that this activation was sustained. We further demonstrated the critical importance of myofibroblast YAP/TAZ in driving progressive scarring in the kidney, lung, and liver, using multiple transgenic models in which YAP and TAZ were either deleted or hyperactivated. Taken together, these data establish the importance of early injury-induced myofibroblast YAP and TAZ activation as a key event driving fibrosis in multiple organs. This information should help guide the development of new antifibrotic YAP/TAZ inhibition strategies.

Authors

Xiaolin He, Monica F. Tolosa, Tianzhou Zhang, Santosh Kumar Goru, Luisa Ulloa Severino, Paraish S. Misra, Caitríona M. McEvoy, Lauren Caldwell, Stephen G. Szeto, Feng Gao, Xiaolan Chen, Cassandra Atin, Victoria Ki, Noah Vukosa, Catherine Hu, Johnny Zhang, Christopher Yip, Adriana Krizova, Jeffrey L. Wrana, Darren A. Yuen

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Figure 1

Progressive myofibroblast YAP/TAZ activation occurs during human kidney fibrogenesis.

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Progressive myofibroblast YAP/TAZ activation occurs during human kidney ...
(A) Serial biopsies collected from the same renal allograft at different times intratransplant and after transplant revealed a progressive increase in interstitial fibrosis, as evidenced by increased picrosirius red staining over time. Black arrows point to increased deposition of collagen (pathologic matrix), whereas black arrowheads identify tubular basement membrane. Black scale bar: 100 μm. (B) Kidney sections were costained with antibodies directed against α-smooth muscle actin (α-SMA, green) and YAP (red) with DAPI (blue) nuclear counterstaining. Each dot in the graph represents a single image (n = 5 images day 0, n = 13 images day 9, and n = 12 images month 2). White arrows point to α-SMA+ myofibroblasts with predominantly nuclear YAP staining. White scale bar: 25 μm. The percentage of α-SMA+ myofibroblasts with predominantly nuclear YAP staining was quantified. (C) Kidney sections were similarly analyzed for nuclear TAZ localization in α-SMA+ myofibroblasts (α-SMA: green, TAZ: red, DAPI: blue). Each dot in the graph represents a single image (n = 4 images day 0, n = 5 images day 9, and n = 11 images month 2). White scale bar: 25 μm. One-way ANOVA with post hoc Tukey’s test was used for comparisons. Data shown as mean ± SEM. *P < 0.05.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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