Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung

Liebler, Janice M.; Marconett, Crystal N.; Juul, Nicholas H.; Wang, Hongjun; Liu, Yixin; Flodby, Per; Laird-Offringa, Ite A.; Minoo, Parviz; Zhou, Baosen

doi:10.1152/ajplung.00337.2015

Cited by 45 publications

(43 citation statements)

References 19 publications

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“…1B). Thus, instead of being lost upon AT1 cell differentiation as suggested previously (16,17), NKX2-1 is expressed in both developing and mature AT1 cells.…”

Section: Resultssupporting

confidence: 64%

“…These mutant cells became airway-like in association with drastic molecular and morphological changes, prompting the question of whether they retained the lung fate, which we addressed by immunostaining for the lung lineage transcription factor NKX2-1 (5). To our surprise, AT1 cells in the control lung had nuclear NKX2-1, different from prior reports that NKX2-1 is a lineage factor during lung specification and branching morphogenesis, but is lost in AT1 cells upon alveolar differentiation (16,17). Intriguingly, NKX2-1 staining in SOX2-expressing mutant AT1 cells was diffuse instead of nuclear,…”

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confidence: 60%

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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.

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146

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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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“…1B). Thus, instead of being lost upon AT1 cell differentiation as suggested previously (16,17), NKX2-1 is expressed in both developing and mature AT1 cells.…”

Section: Resultssupporting

confidence: 64%

mentioning

confidence: 60%

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.

Self Cite

146

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“…Thus, we asked whether this was a characteristic specific to this lineage or if alveolar lineage specification programs are established much earlier in development. To assess this, we determined the relative contribution of AT1 and AT2 progenitor cells to the mature AT1 and AT2 lineages by using established AT1-and AT2specific promoter-driven inducible Cre recombinases, Hopx CreERT and Sftpc CreERT2 (23)(24)(25)(26)(27). We first assessed tamoxifen-independent recombination for each of the well established Cre recombinases and confirmed results previously reported in lung and other organs (23,28,29).…”

Section: Resultsmentioning

confidence: 89%

Early lineage specification defines alveolar epithelial ontogeny in the murine lung

Frank

Penkala

Zepp

et al. 2019

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

129

147

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During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal–distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.

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“…A previous study by our group demonstrated that transdifferentiation of AECs in the BPD model significantly increased at the tissue and cellular levels of AEcs, accompanied by proliferative dysregulation (10). The transdifferentiation of AEC II to AEC I is an important mechanism in lung injury repair (30)(31)(32), but the elevated transdifferentiation level of AECs in the BPD model does not compensate for injury of the lung epithelium, in which AEC II as well as AEC I are structurally and functionally abnormal, resulting in destruction of the blood-gas barrier and opening of the pulmonary epithelial TJs (10). These changes are likely to be associated with excessive dysregulation of transdifferentiation and proliferation of AECs, which provides a novel pathway for further studies on the pathogenesis of BPD.…”

Section: Discussionmentioning

confidence: 95%

Decreased ZONAB expression promotes excessive transdifferentiation of alveolar epithelial cells in hyperoxia-induced bronchopulmonary dysplasia

Hou

Shi

et al. 2018

Int J Mol Med

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Previous studies by our group have confirmed excessive transdifferentiation of alveolar epithelial cells (AECs) in a hyperoxia‑induced bronchopulmonary dysplasia (BPD) model, but the underlying mechanism have remained elusive. The transcription factor zonula occludens 1‑associated nucleic acid binding protein (ZONAB) has the biological functions of inhibition of epithelial cell differentiation and promotion of epithelial cell proliferation. The aim of the present study was to explore the regulatory effect of ZONAB on the transdifferentiation and proliferation of AECs in a model of hyperoxia‑induced lung injury. Newborn Wistar rats were randomly allocated to a model group (inhalation of 85% O2) or a control group (inhalation of normal air), and ZONAB expression in lung tissues was detected at different time‑points. Type II AECs (AEC II) isolated from normal newborn rats were primarily cultured under an atmosphere of 85 or 21% O2, and ZONAB expression in the cells was examined. The primary cells were further transfected with ZONAB plasmid or small interfering (si)RNA and then exposed to hyperoxia, and the indicators for transdifferentiation and proliferation were measured. The present study indicated that ZONAB expression in AEC II of the BPD rats was significantly decreased from 7 days of exposure to hyperoxia onwards. In the AEC II isolated from normal neonatal rats, ZONAB expression in the model group was also reduced compared with that in the control group. After transfection with the plasmid pCMV6‑ZONAB, the expression of aquaporin 5 (type I alveolar epithelial cell marker) decreased and the expression of surfactant protein C (AEC II marker), proliferating‑cell nuclear antigen and cyclin D1 increased, which was opposite to the effects of ZONAB siRNA. Transfection with pCMV6‑ZONAB also alleviated excessive transdifferentiation and inhibited proliferation of AEC II induced by hyperoxia treatment. These results suggest that ZONAB expression in AEC II decreases under hyperoxia conditions, which promotes transdifferentiation and inhibits proliferation of AECs. This may, at least in part, be the underlying mechanism of lung epithelial injury in the hyperoxia-induced BPD model.

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Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung

Cited by 45 publications

References 19 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

Early lineage specification defines alveolar epithelial ontogeny in the murine lung

Decreased ZONAB expression promotes excessive transdifferentiation of alveolar epithelial cells in hyperoxia-induced bronchopulmonary dysplasia

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