Keeping it together: Pulmonary alveoli are maintained by a hierarchy of cellular programs

Logan, Cheryl A.; Desai, Tushar J.

doi:10.1002/bies.201500031

Cited by 27 publications

(21 citation statements)

References 69 publications

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“…Our findings show that TNRC6c plays an essential role in airway sacculation that is upstream of TGFβ, and suggest that it normally acts indirectly by effecting degradation of one or more mRNAs that encode an inhibitor of TGFβ1 and TGFβR2 expression. Identifying these putative mRNAs will be a high priority, since they could be involved in the pathogenesis of neonatal lung diseases in which both alveolar mesenchyme and microvasculature is disrupted, like bronchopulmonary dysplasia, or be harnessed for promoting repair of the gas exchange interface following injury in adult life (Logan and Desai, 2015). …”

Section: Discussionmentioning

confidence: 99%

Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung

Guo

Kazadaeva

Ortega

et al. 2017

Developmental Biology

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GW182 (also known asTNRC6) family members are critically involved in the final effector phase of miRNA-mediated mRNA repression. The three mammalian paralogs, TNRC6a, b and c, are thought to be redundant based on Argonaute (Ago) binding, tethering assays, and RNAi silencing of individual members in cell lines. To test this idea, we generated TNRC6a, b and c knockout mice. TNRC6a mutants die at mid-gestation, while b-and c- deleted mice are born at a Mendelian ratio. However, the majority of TNRC6b and all TNRC6c mutants die within 24 h after birth, the latter with respiratory failure. Necropsy of TNRC6c mutants revealed normal-appearing airways that give rise to abnormally thick-walled distal gas exchange sacs. Immunohistological analysis of mutant lungs demonstrated a normal distribution of bronchiolar and alveolar cells, indicating that loss of TNRC6c did not abrogate epithelial cell differentiation. The cellular kinetics and relative proportions of endothelial, epithelial, and mesenchymal cells were also not altered. However, the underlying capillary network was simplified and endothelial cells had failed to become tightly apposed to the surface epithelium in TNRC6c mutants, presumably causing the observed respiratory failure. TGFβ family mutant mice exhibit a similar lung phenotype of thick-walled air sacs and neonatal lethality, and qRT-PCR confirmed dynamic downregulation of TGFβ1 and TGFβR2 in TNRC6c mutant lungs during sacculation. VEGFR, but not VEGF-A ligand, was also lower, likely reflecting the overall reduced capillary density in TNRC6c mutants. Together, these results demonstrate that GW182 paralogs are not functionally redundant in vivo. Surprisingly, despite regulating a general cellular process, TNRC6c is selectively required only in the distal lung and not until late in gestation for proper expression of the TGFβ family genes that drive sacculation. These results imply a complex and indirect mode of regulation of sacculation by TNRC6c, mediated in part by dynamic transcriptional repression of an inhibitor of TGFβ family gene expression.

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Section: Discussionmentioning

confidence: 99%

Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung

Guo

Kazadaeva

Ortega

et al. 2017

Developmental Biology

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“…Unlike the cells of origin for two other major lung cancer subtypes, adenocarcinoma (alveolar type 2 cells 7 ) and squamous cell carcinoma (presumed to be tracheo-bronchiolar basal cells 8 ), a rare sensory cell type termed pulmonary neuroendocrine cells are the predominant cell of origin for SCLC 9 . Dr. Krasnow’s laboratory has demonstrated that the transformation processes for each of these cell types are similar in that characteristic oncogenes such as EGFR, KRAS , etc.…”

Section: Etiology and Cell Of Origin Of Sclc And Related Neuroendocrimentioning

confidence: 99%

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Bunn

Minna

Augustyn

et al. 2016

Journal of Thoracic Oncology

154

123

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“…Genetic studies in mice support a hierarchy of adult stem cells that can replenish the alveolar gas exchange surface (11), some of which are active only following massive injury (12–14). Under normal homeostatic conditions, the alveolar epithelium is maintained by rare ‘bifunctional’ alveolar epithelial type 2 (AT2) cells, cuboidal cells that retain the surfactant biosynthesis and secretory function of standard ("bulk") AT2 cells (15) but also serve as stem cells that renew the alveolar epithelium throughout the lifespan (16, 17).…”

Section: Introductionmentioning

confidence: 99%

Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells

Nabhan

Brownfield

Harbury

et al. 2018

Science

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617

696

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Lung alveoli are lined by squamous alveolar epithelial type 1 (AT1) epithelial cells that facilitate gas exchange, and neighboring AT2 cells that synthesize and secrete surfactant. Alveoli are maintained by intermittent activation of rare ‘bifunctional’ AT2 cells that retain surfactant biosynthesis function but also serve as stem cells, generating new AT1 cells and self-renewing throughout adult life. While stem cell proliferation is controlled by EGFR/KRAS signaling, how the stem cells are selected, maintained, and the fates of their daughter cells controlled are unknown. Here we show that expression of the Wnt target gene Axin2 in mouse lung identifies a rare, stable subpopulation of AT2 cells with stem cell activity. Many lie near single fibroblasts that express Wnt5a and other Wnt genes, and genetically targeting Wnt secretion by fibroblasts depletes the Axin2+ AT2 stem cell population. Axin2 turns off when daughter cells leave the Wnt niche and transdifferentiate into AT1 cells, and sustaining Wnt signaling blocks transdifferentiation whereas abrogation of Wnt signaling promotes it, both in vivo and in vitro. Upon severe alveolar epithelial injury, Axin2 is induced throughout the AT2 population, recruiting ‘ancillary’ AT2 cells into a progenitor role. Niche expression of Wnt5a and the Wnt secretion mediator Porcupine is unchanged by injury, but Wnt7b and several other Wnt genes are broadly induced along with Porcupine in AT2 cells, and pharmacologic or genetic inhibition of this autocrine Wnt signaling impairs the AT2 proliferative response. The results support a model in which individual AT2 cells reside in single cell fibroblast niches that provide a short-range paracrine (or "juxtacrine") Wnt signal that selects and maintains alveolar stem cell identity and proliferative capacity, while severe injury induces AT2 autocrine Wnt signals that transiently expand the stem cell pool during repair.

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Keeping it together: Pulmonary alveoli are maintained by a hierarchy of cellular programs

Cited by 27 publications

References 69 publications

Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung

Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells

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