Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate

Wang, Yanjie; Tang, Zan; Huang, Huanwei; Li, Jiao; Wang, Zheng; Yu, Yuanyuan; Zhang, Chengwei; Li, Juan; Dai, Huaping; Wang, Fengchao; Cai, Tao; Tang, Nan

doi:10.1073/pnas.1719474115

Cited by 170 publications

(148 citation statements)

References 38 publications

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“…Unlike membrane-localized AT1 markers, HOPX was present in the nucleus and allowed reliable quantification, which showed expression in 28% of GFP cells in the mutant lung versus 95% in the control lung at P10 (n = 3 mice for each genotype; >700 GFP cells/mouse). To extend this analysis to all AT1 cellspecific genes that we compiled from the literature (5,23,26,27), we performed RNA-seq of purified genetically labeled AT1 cells from P5 control and Nkx2-1 mutant lungs. We found down-regulation of 25 out of 27 AT1 genes, such as Sema3a, Clic5, Samhd1, Rtkn2, Cav1, Hopx, Ager, and Aqp5 ( Fig.…”

Section: Nkx2-1 Is Necessary For 3 Defining Features Of Developing Atmentioning

confidence: 99%

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

Little

Gerner-Mauro

Flodby

et al. 2019

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

132

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The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and 3D imaging, we found that NK homeobox 2-1 (Nkx2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose 3 defining features—molecular markers, expansive morphology, and cellular quiescence—leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same 3 defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal (GI) genes and form dense microvilli-like structures apically. Single-cell RNA-seq supports a linear transformation of Nkx2-1 mutant AT1 cells toward a GI fate. Whole lung ChIP-seq shows NKX2-1 binding to 68% of genes that are down-regulated upon Nkx2-1 deletion, including 93% of known AT1 genes, but near-background binding to up-regulated genes. Our results place NKX2-1 at the top of the AT1 cell transcriptional hierarchy and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type.

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Section: Nkx2-1 Is Necessary For 3 Defining Features Of Developing Atmentioning

confidence: 99%

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

Little

Gerner-Mauro

Flodby

et al. 2019

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

132

View full text Add to dashboard Cite

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“…But in human lungs, the presence of basal cells is apparent in terminal bronchiole in addition to proximal airways [23]. In addition, AT1 cells, previously thought to be terminally differentiated, have been shown to exhibit plasticity potential to dedifferentiate into AT2 cells in a mouse model of partial pneumonectomy [24,25]. Thus, injury-specific repair mechanisms may exist for rapid recovery of alveolar epithelia to secure the gas exchange function by accelerating AT2 cell regeneration.…”

Section: Stem/progenitor Cells That Generatementioning

confidence: 99%

Organoids as a Powerful Model for Respiratory Diseases

Liu

Wu²,

Sun³

et al. 2020

Stem Cells International

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Insults to the alveoli usually lead to inefficient gas exchange or even respiratory failure, which is difficult to model in animal studies. Over the past decade, stem cell-derived self-organizing three-dimensional organoids have emerged as a new avenue to recapitulate respiratory diseases in a dish. Alveolar organoids have improved our understanding of the mechanisms underlying tissue homeostasis and pathological alterations in alveoli. From this perspective, we review the state-of-the-art technology on establishing alveolar organoids from endogenous lung epithelial stem/progenitor cells or pluripotent stem cells, as well as the use of alveolar organoids for the study of respiratory diseases, including idiopathic pulmonary fibrosis, tuberculosis infection, and respiratory virus infection. We also discuss challenges that need to be overcome for future application of alveolar organoids in individualized medicine.

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“…Moreover, the unaltered protein levels of Cav1 and SFTPC in P1 and P3 CPEB2-KO lungs (Additional file 1: Figure S4b) also reconfirmed the unaffected AECI and AECII populations in the absence of CPEB2. Due to the extended morphology of AECIs, a nuclear marker of AECIs, homeodomain-only protein x (Hopx) [49], was also examined. We observed not all Cav1 + AECIs expressing Hopx but the populations of Hopx-positive (Hopx + ) AECIs in P3 WT and KO lungs were comparable (Additional file 1: Figure S4c, c').…”

Section: Cpeb2 Deficiency Reduces Cell Proliferation and Myf Populatimentioning

confidence: 99%

CPEB2-activated PDGFRα mRNA translation contributes to myofibroblast proliferation and pulmonary alveologenesis

et al. 2020

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Background: Alveologenesis is the final stage of lung development to form air-exchanging units between alveoli and blood vessels. Genetic susceptibility or hyperoxic stress to perturb this complicated process can cause abnormal enlargement of alveoli and lead to bronchopulmonary dysplasia (BPD)-associated emphysema. Plateletderived growth factor receptor α (PDGFRα) signaling is crucial for alveolar myofibroblast (MYF) proliferation and its deficiency is associated with risk of BPD, but posttranscriptional mechanisms regulating PDGFRα synthesis during lung development remain largely unexplored. Cytoplasmic polyadenylation element-binding protein 2 (CPEB2) is a sequence-specific RNA-binding protein and translational regulator. Because CPEB2-knockout (KO) mice showed emphysematous phenotypes, we investigated how CPEB2-controlled translation affects pulmonary development and function. Methods: Respiratory and pulmonary functions were measured by whole-body and invasive plethysmography. Histological staining and immunohistochemistry were used to analyze morphology, proliferation, apoptosis and cell densities from postnatal to adult lungs. Western blotting, RNA-immunoprecipitation, reporter assay, primary MYF culture and ectopic expression rescue were performed to demonstrate the role of CPEB2 in PDGFRα mRNA translation and MYF proliferation. Results: Adult CPEB2-KO mice showed emphysema-like dysfunction. The alveolar structure in CPEB2-deficient lungs appeared normal at birth but became simplified through the alveolar stage of lung development. In CPEB2-null mice, we found reduced proliferation of MYF progenitors during alveolarization, abnormal deposition of elastin and failure of alveolar septum formation, thereby leading to enlarged pulmonary alveoli. We identified that CPEB2 promoted PDGFRα mRNA translation in MYF progenitors and this positive regulation could be disrupted by H 2 O 2 , a hyperoxia-mimetic treatment. Moreover, decreased proliferating ability in KO MYFs due to insufficient PDGFRα expression was rescued by ectopic expression of CPEB2, suggesting an important role of CPEB2 in upregulating PDGFRα signaling for pulmonary alveologenesis. Conclusions: CPEB2-controlled translation, in part through promoting PDGFRα expression, is indispensable for lung development and function. Since defective pulmonary PDGFR signaling is a key feature of human BPD, CPEB2 may be a risk factor for BPD.

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Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate

Cited by 170 publications

References 38 publications

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

Organoids as a Powerful Model for Respiratory Diseases

CPEB2-activated PDGFRα mRNA translation contributes to myofibroblast proliferation and pulmonary alveologenesis

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