Repair and Regeneration of the Respiratory System: Complexity, Plasticity, and Mechanisms of Lung Stem Cell Function

Hogan, Brigid L.M.; Barkauskas, Christina E.; Chapman, Harold A.; Epstein, Jonathan A.; Jain, Rajan; Hsia, Connie C. W.; Niklason, Laura E.; Calle, Elizabeth A.; Le, Andrew; Randell, Scott H.; Rock, Jason R.; Snitow, Melinda; Krummel, Matthew F.; Stripp, Barry R.; Vu, Thiennu H.; White, Eric S.; Whitsett, Jeffrey A.; Morrisey, Edward E.

doi:10.1016/j.stem.2014.07.012

Cited by 750 publications

(766 citation statements)

References 139 publications

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“…Pulmonary fibrosis and emphysema patients have also been noted to have abnormally short telomeres in AEC2s (6, 7, 13). These observations, along with AEC2s' regenerative capacity (14)(15)(16), led us to hypothesize that telomere dysfunction is sufficient to provoke AEC2 failure and that this event drives lung disease pathogenesis.…”

mentioning

confidence: 99%

Telomere dysfunction causes alveolar stem cell failure

Alder

Barkauskas²,

Limjunyawong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

266

258

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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.

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mentioning

confidence: 99%

Telomere dysfunction causes alveolar stem cell failure

Alder

Barkauskas²,

Limjunyawong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

266

258

View full text Add to dashboard Cite

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“…MCE are characterised by the presence of at least two cell types: mucus-secreting (goblet) cells and multiciliated cells (MCCs) with motile cilia that distribute and mobilise the mucus along the epithelial surface. The mammalian airway MCE also contains basally located cells that have stem cell-like features and are responsible for renewal and maintenance of the tissue (Hajj et al, 2007;Hogan et al, 2014;Rock et al, 2009). The cellular and molecular events controlling human airway MCE formation and renewal are incompletely understood, largely owing to the poor accessibility and experimental amenability of this tissue.…”

Section: Introductionmentioning

confidence: 99%

BMP signalling controls the construction of vertebrate mucociliary epithelia

et al. 2015

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Despite the importance of mucociliary epithelia in animal physiology, the mechanisms controlling their establishment are poorly understood. Using the developing Xenopus epidermis and regenerating human upper airways, we reveal the importance of BMP signalling for the construction of vertebrate mucociliary epithelia. In Xenopus, attenuation of BMP activity is necessary for the specification of multiciliated cells (MCCs), ionocytes and small secretory cells (SSCs). Conversely, BMP activity is required for the proper differentiation of goblet cells. Our data suggest that the BMP and Notch pathways interact to control fate choices in the developing epidermis. Unexpectedly, BMP activity is also necessary for the insertion of MCCs, ionocytes and SSCs into the surface epithelium. In human, BMP inhibition also strongly stimulates the formation of MCCs in normal and pathological (cystic fibrosis) airway samples, whereas BMP overactivation has the opposite effect. This work identifies the BMP pathway as a key regulator of vertebrate mucociliary epithelium differentiation and morphogenesis.

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“…Indeed, procedures incorporating other acellular material and polymeric scaffolds have been reported since the turn of the millennium, while engineered three-dimensional (3D) in vitro models of the respiratory tract can be seen in the literature dating back to the 1970s (12). Recent advances in our understanding of lung stem cell biology have also identified potential pools of cell types that could be utilised for regenerative purposes in line with tissue engineered biomaterials (13).…”

Section: Introductionmentioning

confidence: 99%