TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Xin Pan, Lan Wang (), Juntang Yang, Yingge Li, Min Xu, Chenxi Liang, Lulu Liu, Zhongzheng Li, Cong Xia, Jiaojiao Pang, Mengyuan Wang, Meng Li, Saiya Guo, Peishuo Yan, Chen Ding, Ivan O. Rosas and Guoying Yu ()
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Xin Pan: Henan Normal University
Lan Wang: Henan Normal University
Juntang Yang: Henan Normal University
Yingge Li: Henan Normal University
Min Xu: Henan Normal University
Chenxi Liang: Henan Normal University
Lulu Liu: Henan Normal University
Zhongzheng Li: Henan Normal University
Cong Xia: Henan Normal University
Jiaojiao Pang: Henan Normal University
Mengyuan Wang: Henan Normal University
Meng Li: Henan Normal University
Saiya Guo: Henan Normal University
Peishuo Yan: Henan Normal University
Chen Ding: Fudan University
Ivan O. Rosas: Baylor College of Medicine
Guoying Yu: Henan Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

Date: 2024
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DOI: 10.1038/s41467-024-52827-z

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