TRβ Activation Confers AT2-to-AT1 Cell Differentiation and Anti-fibrosis During Lung Repair Via KLF2 and CEBPA

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Oct 7

PMID 39375377

Authors

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

Guoying Yu

Affiliations

Soon will be listed here.

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.

References

Schiller H, Montoro D, Simon L, Rawlins E, Meyer K, Strunz M . The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease. Am J Respir Cell Mol Biol. 2019; 61(1):31-41. PMC: 6604220. DOI: 10.1165/rcmb.2018-0416TR. View

Strunz M, Simon L, Ansari M, Kathiriya J, Angelidis I, Mayr C . Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat Commun. 2020; 11(1):3559. PMC: 7366678. DOI: 10.1038/s41467-020-17358-3. View

Picard M . Why Do We Care More About Disease than Health?. Phenomics. 2023; 2(3):145-155. PMC: 9590501. DOI: 10.1007/s43657-021-00037-8. View

Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, Tang J . Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight. 2016; 1(20):e90558. PMC: 5135277. DOI: 10.1172/jci.insight.90558. View

Zacharias W, Frank D, Zepp J, Morley M, Alkhaleel F, Kong J . Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature. 2018; 555(7695):251-255. PMC: 6020060. DOI: 10.1038/nature25786. View

Kumar P, Hu Y, Yamamoto Y, Hoe N, Wei T, Mu D . Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell. 2011; 147(3):525-38. PMC: 4040224. DOI: 10.1016/j.cell.2011.10.001. View

Martinez F, Collard H, Pardo A, Raghu G, Richeldi L, Selman M . Idiopathic pulmonary fibrosis. Nat Rev Dis Primers. 2017; 3:17074. DOI: 10.1038/nrdp.2017.74. View

Basil M, Katzen J, Engler A, Guo M, Herriges M, Kathiriya J . The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future. Cell Stem Cell. 2020; 26(4):482-502. PMC: 7128675. DOI: 10.1016/j.stem.2020.03.009. View

Barkauskas C, Cronce M, Rackley C, Bowie E, Keene D, Stripp B . Type 2 alveolar cells are stem cells in adult lung. J Clin Invest. 2013; 123(7):3025-36. PMC: 3696553. DOI: 10.1172/JCI68782. View

10.

Nabhan A, Brownfield D, Harbury P, Krasnow M, Desai T . Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science. 2018; 359(6380):1118-1123. PMC: 5997265. DOI: 10.1126/science.aam6603. View

11.

Choi J, Park J, Tsagkogeorga G, Yanagita M, Koo B, Han N . Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration. Cell Stem Cell. 2020; 27(3):366-382.e7. PMC: 7487779. DOI: 10.1016/j.stem.2020.06.020. View

12.

Kobayashi Y, Tata A, Konkimalla A, Katsura H, Lee R, Ou J . Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol. 2020; 22(8):934-946. PMC: 7461628. DOI: 10.1038/s41556-020-0542-8. View

13.

Kasper M, Haroske G . Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol. 1996; 11(2):463-83. View

14.

Melms J, Biermann J, Huang H, Wang Y, Nair A, Tagore S . A molecular single-cell lung atlas of lethal COVID-19. Nature. 2021; 595(7865):114-119. PMC: 8814825. DOI: 10.1038/s41586-021-03569-1. View

15.

Lv T, Meng F, Yu M, Huang H, Lin X, Zhao B . Defense of COVID-19 by Human Organoids. Phenomics. 2022; 1(3):113-128. PMC: 8277987. DOI: 10.1007/s43657-021-00015-0. View

16.

Boelen A, Kwakkel J, Fliers E . Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev. 2011; 32(5):670-93. DOI: 10.1210/er.2011-0007. View

17.

Fliers E, Bianco A, Langouche L, Boelen A . Thyroid function in critically ill patients. Lancet Diabetes Endocrinol. 2015; 3(10):816-25. PMC: 4979220. DOI: 10.1016/S2213-8587(15)00225-9. View

18.

de Vries E, Fliers E, Boelen A . The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015; 225(3):R67-81. DOI: 10.1530/JOE-15-0133. View

19.

Gereben B, McAninch E, Ribeiro M, Bianco A . Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol. 2015; 11(11):642-652. PMC: 5003781. DOI: 10.1038/nrendo.2015.155. View

20.

Ortiga-Carvalho T, Sidhaye A, Wondisford F . Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol. 2014; 10(10):582-91. PMC: 4578869. DOI: 10.1038/nrendo.2014.143. View