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Telomere dysfunction causes alveolar stem cell failure

  1. Mary Armaniosa,b,g,2
  1. aDepartment of Oncology,
  2. bSidney Kimmel Comprehensive Cancer Center, and
  3. gMcKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
  4. Departments of cMedicine and
  5. fCell Biology, Duke University School of Medicine, Durham, NC 27710;
  6. dDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; and
  7. eDivision of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045

  1. Contributed by Brigid L. M. Hogan, March 11, 2015 (sent for review February 3, 2015)

Significance

Idiopathic pulmonary fibrosis and emphysema are leading causes of mortality, but there are no effective therapies. Mutations in telomerase are the most common identifiable risk factor for idiopathic pulmonary fibrosis. They also predispose to severe emphysema in smokers, occurring at a frequency similar to α-1 antitrypsin deficiency. The work shown here points to alveolar stem cell senescence as a driver of these pathologies. Epithelial stem cell failure was associated with secondary inflammatory recruitment and exquisite susceptibility to injury from “second hits.” The findings suggest that efforts to reverse the stem cell failure state directly, rather than its secondary consequences, may be an effective therapy approach in telomere-mediated lung disease.

Abstract

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

Footnotes

  • ↵1Present address: Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602.

  • ↵2To whom correspondence may be addressed. Email: marmani1{at}jhmi.edu or brigid.hogan{at}duke.edu.

  • Author contributions: J.K.A., C.E.B., B.L.M.H., and M.A. designed research; J.K.A., C.E.B., N.L., S.E.S., F.K., and R.M.T. performed research; J.K.A., C.E.B., N.L., B.L.M.H., and W.M. contributed new reagents/analytic tools; J.K.A., C.E.B., N.L., S.E.S., B.L.M.H., W.M., and M.A. analyzed data; and J.K.A. and M.A. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: Microarray data compliant with the minimum information about a microarray experiment (MIAME) standard have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE56892).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1504780112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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