Telomere dysfunction causes alveolar stem cell failure

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.

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

“…Remarkably, the epithelial-derived DNA damage signal is sufficient to recruit macrophages and T cells, an inflammatory response that resembles what is seen in smokers and in patients with COPD (38). The current working model that synthesizes the findings of these studies is that short telomere-mediated stem cell senescence upregulates the expression of proinflammatory cytokines, which in turn drives inflammation (38). In effect, the inflammation in this form of emphysema is a secondary bystander caused by an upstream defect in stem cell senescence rather than a primary driver per se (38).…”

“…In that milieu, at least a subset of type 2 alveolar epithelial cells (AEC2s) function as a facultative progenitor for new AEC2s as well as type 1 cells (37). The role of stem cell failure in lung disease susceptibility has been addressed experimentally (38). Co-culture experiments showed an AEC2-intrinsic regenerative defect in which only AEC2s with short telomeres, not mesenchymal cells, fail to support alveolar organoid formation.…”

“…Co-culture experiments showed an AEC2-intrinsic regenerative defect in which only AEC2s with short telomeres, not mesenchymal cells, fail to support alveolar organoid formation. When telomere dysfunction is induced in vivo by deletion of the telomere-protective protein Trf2 specifically in AEC2s, the resultant DNA damage response induces senescence and consequent lung remodeling (38). Remarkably, the epithelial-derived DNA damage signal is sufficient to recruit macrophages and T cells, an inflammatory response that resembles what is seen in smokers and in patients with COPD (38).…”

“…When telomere dysfunction is induced in vivo by deletion of the telomere-protective protein Trf2 specifically in AEC2s, the resultant DNA damage response induces senescence and consequent lung remodeling (38). Remarkably, the epithelial-derived DNA damage signal is sufficient to recruit macrophages and T cells, an inflammatory response that resembles what is seen in smokers and in patients with COPD (38). The current working model that synthesizes the findings of these studies is that short telomere-mediated stem cell senescence upregulates the expression of proinflammatory cytokines, which in turn drives inflammation (38).…”

“…The current working model that synthesizes the findings of these studies is that short telomere-mediated stem cell senescence upregulates the expression of proinflammatory cytokines, which in turn drives inflammation (38). In effect, the inflammation in this form of emphysema is a secondary bystander caused by an upstream defect in stem cell senescence rather than a primary driver per se (38). Such a paradigm predicts a modest benefit for antiinflammatory approaches in subsets of patients in whom telomere shortening is the primary driver of disease.…”