Consequences of Telomere Dysfunction in Fibroblasts, Club and Basal Cells for Lung Fibrosis Development

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 6

PMID 36202783

Authors

Sergio Pineiro-Hermida

Paula Martinez

Giuseppe Bosso

Juana Maria Flores

Sarita Saraswati

Jane Connor

Raphael Lemaire

Maria A Blasco

Affiliations

Soon will be listed here.

Abstract

TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells. TRF1 deficiency in lung fibroblasts, club and basal cells induced telomeric damage, proliferative defects, cell cycle arrest and apoptosis. While Trf1 deletion in fibroblasts does not spontaneously lead to lung pathologies, upon bleomycin challenge exacerbates lung fibrosis. Unlike in females, Trf1 deletion in club and basal cells from male mice resulted in lung inflammation and airway remodeling. Here, we show that depletion of TRF1 in fibroblasts, Club and basal cells does not lead to interstitial lung fibrosis, underscoring ATII cells as the relevant cell type for the origin of interstitial fibrosis. Our findings contribute to a better understanding of proper telomere protection in lung tissue homeostasis.

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References

Rawlins E, Okubo T, Xue Y, Brass D, Auten R, Hasegawa H . The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell. 2009; 4(6):525-34. PMC: 2730729. DOI: 10.1016/j.stem.2009.04.002. View

Cordoba-Lanus E, Cazorla-Rivero S, Espinoza-Jimenez A, de-Torres J, Pajares M, Aguirre-Jaime A . Telomere shortening and accelerated aging in COPD: findings from the BODE cohort. Respir Res. 2017; 18(1):59. PMC: 5390353. DOI: 10.1186/s12931-017-0547-4. View

Somayaji R, Chalmers J . Just breathe: a review of sex and gender in chronic lung disease. Eur Respir Rev. 2022; 31(163). PMC: 9488531. DOI: 10.1183/16000617.0111-2021. View

Zheng B, Zhang Z, Black C, de Crombrugghe B, Denton C . Ligand-dependent genetic recombination in fibroblasts : a potentially powerful technique for investigating gene function in fibrosis. Am J Pathol. 2002; 160(5):1609-17. PMC: 1850857. DOI: 10.1016/S0002-9440(10)61108-X. View

Bosso G, Lanuza-Gracia P, Pineiro-Hermida S, Yilmaz M, Serrano R, Blasco M . Early differential responses elicited by BRAF in adult mouse models. Cell Death Dis. 2022; 13(2):142. PMC: 8831492. DOI: 10.1038/s41419-022-04597-z. View

Raghu G, Remy-Jardin M, Myers J, Richeldi L, Ryerson C, Lederer D . Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018; 198(5):e44-e68. DOI: 10.1164/rccm.201807-1255ST. View

Hou J, Shi J, Chen L, Lv Z, Chen X, Cao H . M2 macrophages promote myofibroblast differentiation of LR-MSCs and are associated with pulmonary fibrogenesis. Cell Commun Signal. 2018; 16(1):89. PMC: 6260991. DOI: 10.1186/s12964-018-0300-8. View

Tompkins D, Besnard V, Lange A, Wert S, Keiser A, Smith A . Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells. PLoS One. 2009; 4(12):e8248. PMC: 2788414. DOI: 10.1371/journal.pone.0008248. View

Birch J, Anderson R, Correia-Melo C, Jurk D, Hewitt G, Marques F . DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2015; 309(10):L1124-37. PMC: 4652155. DOI: 10.1152/ajplung.00293.2015. View

10.

Schneider R, Garrobo I, Foronda M, Palacios J, Marion R, Flores I . TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells. Nat Commun. 2013; 4:1946. DOI: 10.1038/ncomms2946. View

11.

Yang Y, Riccio P, Schotsaert M, Mori M, Lu J, Lee D . Spatial-Temporal Lineage Restrictions of Embryonic p63 Progenitors Establish Distinct Stem Cell Pools in Adult Airways. Dev Cell. 2018; 44(6):752-761.e4. PMC: 5875454. DOI: 10.1016/j.devcel.2018.03.001. View

12.

Alfaro-Arnedo E, Lopez I, Pineiro-Hermida S, Ucero A, Gonzalez-Barcala F, Salgado F . IGF1R as a Potential Pharmacological Target in Allergic Asthma. Biomedicines. 2021; 9(8). PMC: 8389607. DOI: 10.3390/biomedicines9080912. View

13.

Everaerts S, Lammertyn E, Martens D, De Sadeleer L, Maes K, van Batenburg A . The aging lung: tissue telomere shortening in health and disease. Respir Res. 2018; 19(1):95. PMC: 5948770. DOI: 10.1186/s12931-018-0794-z. View

14.

Stanley S, Chen J, Podlevsky J, Alder J, Hansel N, Mathias R . Telomerase mutations in smokers with severe emphysema. J Clin Invest. 2015; 125(2):563-70. PMC: 4319417. DOI: 10.1172/JCI78554. View

15.

Morrisey E . Basal Cells in Lung Development and Repair. Dev Cell. 2018; 44(6):653-654. DOI: 10.1016/j.devcel.2018.03.004. View

16.

Di Gregorio J, Robuffo I, Spalletta S, Giambuzzi G, De Iuliis V, Toniato E . The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders. Front Cell Dev Biol. 2021; 8:607483. PMC: 7779530. DOI: 10.3389/fcell.2020.607483. View

17.

Diotti R, Loayza D . Shelterin complex and associated factors at human telomeres. Nucleus. 2011; 2(2):119-35. PMC: 3127094. DOI: 10.4161/nucl.2.2.15135. View

18.

Lomas N, Watts K, Akram K, Forsyth N, Spiteri M . Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers. Int J Clin Exp Pathol. 2012; 5(1):58-71. PMC: 3267487. View

19.

Liu Z, Liao F, Scozzi D, Furuya Y, Pugh K, Hachem R . An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants. JCI Insight. 2019; 5. PMC: 6538316. DOI: 10.1172/jci.insight.124732. View

20.

Voltz J, Card J, Carey M, Degraff L, Ferguson C, Flake G . Male sex hormones exacerbate lung function impairment after bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2008; 39(1):45-52. PMC: 2438447. DOI: 10.1165/rcmb.2007-0340OC. View