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TAZ is required for lung alveolar epithelial cell differentiation after injury
Tianhe Sun, … , Anwesha Dey, Joseph R. Arron
Tianhe Sun, … , Anwesha Dey, Joseph R. Arron
Published June 18, 2019
Citation Information: JCI Insight. 2019;4(14):e128674. https://doi.org/10.1172/jci.insight.128674.
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Research Article Pulmonology Stem cells

TAZ is required for lung alveolar epithelial cell differentiation after injury

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Abstract

The lung is a relatively quiescent organ during homeostasis but has a remarkable capacity for repair after injury. Alveolar epithelial type I cells (AEC1s) line airspaces and mediate gas exchange. After injury, they are regenerated by differentiation from their progenitors — alveolar epithelial type II cells (AEC2s) — which also secrete surfactant to maintain surface tension and alveolar patency. While recent studies showed that the maintenance of AEC2 stemness is Wnt dependent, the molecular mechanisms underlying AEC2-AEC1 differentiation in adult lung repair are still incompletely understood. Here, we show that WWTR1 (TAZ) plays a crucial role in AEC differentiation. Using an in vitro organoid culture system, we found that tankyrase inhibition can efficiently block AEC2-AEC1 differentiation, and this effect was due to the inhibition of TAZ. In a bleomycin-induced lung injury model, conditional deletion of TAZ in AEC2s dramatically reduced AEC1 regeneration during recovery, leading to exacerbated alveolar lesions and fibrosis. In patients with idiopathic pulmonary fibrosis (IPF), decreased blood levels of the receptor for advanced glycation end products (RAGE), a biomarker of AEC1 health, were associated with more rapid disease progression. Our findings implicate TAZ as a critical factor involved in AEC2-to-AEC1 differentiation, and hence the maintenance of alveolar integrity after injury.

Authors

Tianhe Sun, Zhiyu Huang, Hua Zhang, Clara Posner, Guiquan Jia, Thirumalai R. Ramalingam, Min Xu, Hans Brightbill, Jackson G. Egen, Anwesha Dey, Joseph R. Arron

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Figure 6

Fibrosis is increased in TAZ-deficient mice in response to bleomycin injury in regions with defective epithelial repair.

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Fibrosis is increased in TAZ-deficient mice in response to bleomycin inj...
(A) FL images show mouse lungs examined untreated or 22 days after bleomycin delivery. Lungs were immunostained for RAGE (AEC1) and collagen I. Arrows indicate fibrotic lesions with dense collagen deposition. Close-up images show more extensive alveolar epithelial loss (yellow polygons) in SPC-Taz.KO-Tm mouse lungs. (B) Deuterated hydroxyproline levels (mean ± SD) were measured as an indicator of newly synthesized collagen. **P < 0.01 (1-way ANOVA with Tukey’s test); n = 5 mice (each saline group); n = 15 mice (WT, BLM); n = 11 mice (SPC-Taz.KO, BLM). (C and D) SPC-WT-Tm and SPC-Taz.KO-Tm mice were examined 3 months after tamoxifen (Tmx) induction. Lungs were immunostained for RAGE and AEC2 lineage trace was indicated by tdTomato+. Circles delineate newly regenerated alveoli, identified by squamous AEC1s expressing AEC2 lineage tracer (tdTomato+). High-magnification insets show comparable morphologies of newly regenerated AEC1s in these two strains. (D) Quantification shows the percentage (mean ± SD) of newly regenerated alveoli in SPC-WT-Tm mice (n = 3 mice with total 3,656 alveoli counted) and SPC-Taz.KO mice (n = 3 mice with total 4,425 alveoli counted). NS (unpaired 2-tailed Student’s t tests). Scale bars: 0.5 mm (A); 100 μm (A, enlarged); 30 μm (C).

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