Epithelial Vegfa specifies a distinct endothelial population in the mouse lung

Ellis, Lisandra Vila; Cain, Margo P.; Hutchison, Vera; Flodby, Per; Crandall, Edward D.; Borok, Zea; Zhou, Bin; Ostrin, Edwin J.; Wythe, Joshua D.; Chen, Jichao

doi:10.1101/840033

Cited by 19 publications

(45 citation statements)

References 55 publications

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“…The expression of the proliferation marker was observed in a few iAT1 cells at single-cell resolution ( Figure 7D,E), but, since the FD-AO culture was started only with iAT2 cells, it would be considered that most iAT1 cells differentiated from iAT2 cells. While recent reports indicated that AT1 cells expressed VEGFA and were a heterogeneous population including IGFBP2 + AT1 cells, 22,23 we were not able to identify this subpopulation of iAT1 cells, suggesting that XAV-939 would homogeneously induce iAT1 cells ( Figure 7E). Although in vitro regeneration models 5,15,24 and an iPSC differentiation model 24 cells that were not treated with XAV-939 treatment ( Figure 5E), suggesting that there is another endogenous mechanism through which Wnt signaling is inhibited and iAT2-to-iAT1 differentiation is promoted.…”

Section: Discussioncontrasting

confidence: 77%

Directed induction of alveolar type I cells derived from pluripotent stem cells via Wnt signaling inhibition

et al. 2020

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Alveologenesis is a developmental step involving the expansion of the lung surface area which is essential for gas exchange. The gas exchange process is mediated by alveolar type I (AT1) cells, which are known to be differentiated from alveolar type II (AT2) or bipotent cells. Due to the difficulty of isolating and culturing primary AT1 cells, the mechanism underlying their differentiation is not completely understood. We performed single-cell RNA sequencing (scRNA-seq) of fibroblast-dependent alveolar organoids (FD-AOs), including human induced pluripotent stem cell (hiPSC)-derived epithelial cells and fetal lung fibroblasts, and identified hiPSC-derived AT1 (iAT1) cells. A comparison of the FD-AOs and fibroblast-free alveolar organoids showed that iAT1 cells were mainly present in the FD-AOs. Importantly, the transcriptomes of iAT1 cells were remarkably similar to those of primary AT1 cells. Additionally, XAV-939, a tankyrase inhibitor, increased iAT1 cells in passaged FD-AOs, suggesting that these cells were differentiated from hiPSC-derived AT2 (iAT2) cells through the inhibition of canonical Wnt signaling. Consequently, our scRNAseq data allowed us to define iAT1 cells and identify FD-AOs as a useful model for investigating the mechanism underlying human AT1 cell differentiation from AT2 cells in vitro.

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Section: Discussioncontrasting

confidence: 77%

Directed induction of alveolar type I cells derived from pluripotent stem cells via Wnt signaling inhibition

et al. 2020

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“…4E, F and Table S2). These changes were confirmed in a metagene analysis using AT1 and AT2 gene signatures derived from scRNA-seq of E19 lungs (26), as well as our published 119 progenitor genes (11) ( Fig. 4G, Table S3, Table S4).…”

Section: Single-cell Rna-seq Profiling Of Post-lung-specification Lefsupporting

confidence: 78%

“…Raw data have been deposited in GEO under the accession number GSE144170. AT1 and AT2 gene lists are from the following dataset: GSE124325 (26).…”

Section: Cell Dissociation and Facs For Scrna-seqmentioning

confidence: 99%

Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors

Gerner-Mauro

Akiyama

Chen

2020

Preprint

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In multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multi-member paralogs, as exemplified by the 4 obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the dauntingly complex genetics involved. Using the developing mouse lung as a model system, we generate 2 quadruple conditional knockouts and myriad triple and double combinations, and show that the 4 Lef/Tcf genes function redundantly in the presence of at least 2 Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Pre-lung-specification, pan-epithelial double knockouts have no lung phenotype, triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas, and the quadruple knockout barely forms a lung, resembling the Ctnnb1 mutant. Postlung-specification deletion of all 4 Lef/Tcf genes leads to branching defects, downregulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the corresponding Ctnnb1 mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors and represents, to our knowledge, the first in vivo analysis of cell-type-specific genetic redundancy among the 4 Lef/Tcf paralogs. SIGNIFICANCE STATEMENTParalogs represent genetic redundancy and survive purifying selection by evolving overlapping and distinct functions. In multicellular organisms, such functional diversification can manifest as tissue and cell type specific expression, which masks possible selective pressure for genetic redundancy within a single cell type. Using in vivo genetic and genomic analyses, we show that although the 4 mammalian Lef/Tcf transcription factors have evolved organ-specific functions, they function additively and redundantly, depending on gene dosage, to promote lung epithelial progenitors and do so in a monotonic, positive manner with beta-Catenin in the canonical Wnt signaling pathway.

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“…In the absence of Car4 ECs, despite the normal appearance of myofibroblasts, alveolar space is aberrantly enlarged. These observations indicate a signaling role of AT1 cells [ 79 ]. Importantly, overexpression of VEGF in newborn mice induces inducible nitric oxide synthase (iNOS) and eNOS-dependent lung simplification, pulmonary edema, and oxidant stress.…”

Section: Deregulated Signaling Pathwaysmentioning

confidence: 99%

Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

Mathew

2020

Children

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The alveolar and vascular developmental arrest in the premature infants poses a major problem in the management of these infants. Although, with the current management, the survival rate has improved in these infants, but bronchopulmonary dysplasia (BPD) is a serious complication associated with a high mortality rate. During the neonatal developmental period, these infants are vulnerable to stress. Hypoxia, hyperoxia, and ventilation injury lead to oxidative and inflammatory stress, which induce further damage in the lung alveoli and vasculature. Development of pulmonary hypertension (PH) in infants with BPD worsens the prognosis. Despite considerable progress in the management of premature infants, therapy to prevent BPD is not yet available. Animal experiments have shown deregulation of multiple signaling factors such as transforming growth factorβ (TGFβ), connective tissue growth factor (CTGF), fibroblast growth factor 10 (FGF10), vascular endothelial growth factor (VEGF), caveolin-1, wingless & Int-1 (WNT)/β-catenin, and elastin in the pathogenesis of BPD. This article reviews the signaling pathways entailed in the pathogenesis of BPD associated with PH and the possible management.

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Epithelial Vegfa specifies a distinct endothelial population in the mouse lung

Cited by 19 publications

References 55 publications

Directed induction of alveolar type I cells derived from pluripotent stem cells via Wnt signaling inhibition

Directed induction of alveolar type I cells derived from pluripotent stem cells via Wnt signaling inhibition

Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors

Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

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