A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

He, Peng; Lim, Kyungtae; Sun, Dawei; Pett, Jan Patrick; Jeng, Quitz; Polański, Krzysztof; Dong, Ziqi; Bolt, Liam; Richardson, Laura L.; Mamanova, Lira; Dąbrowska, Monika; Wilbrey-Clark, Anna; Madissoon, Elo; Tuong, Zewen Kelvin; Dann, Emma; Suo, Chenqu; Goh, Issac; Yoshida, Masahiro; Nikolić, Marko; Janes, Sam M.; He, Xiaoling; Barker, Roger A.; Teichmann, Sarah A.; Marioni, John C.; Meyer, Kerstin B.; Rawlins, Emma L.

doi:10.1016/j.cell.2022.11.005

Cited by 103 publications

(136 citation statements)

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“…Two independent inducible CRISPRi parental organoid lines were transduced with 2 different non‐targeting control gRNAs, two different SOX9 gRNAs and two different SOX2 gRNAs, respectively. Organoids were supplemented with Dox/TMP for 5 day before harvesting for RNA‐seq. Venn Diagram showing the overlapping number of differentially expressed (DE) genes in SOX9 knock‐down organoids from different parental lines. All SOX9 positively and negatively regulated genes were used to score against an scRNA‐Seq dataset from 9 to 11 pcw human foetal lung epithelium (left panel, preprint: He et al , 2022). SOX9 negatively regulated genes were primarily enriched in secretory lineage populations (middle panel).…”

Section: Resultsmentioning

confidence: 99%

“…To test whether the SOX9 knock‐down cells altered their differentiation status, we took advantage of our human foetal lung scRNA‐seq dataset (preprint: He et al , 2022). We subset the human foetal lung scRNA‐seq data from 9 to 11 postconception weeks (pcw) and used all SOX9 positively and negatively regulated genes to score the epithelial compartment (Fig 2H).…”

Section: Resultsmentioning

confidence: 99%

“…Upregulated and downregulated genes in SOX9 knock‐down DE gene list and SOX9 direct transcriptional target list were used to score epithelial cells from 9 to11 pcw human foetal lungs (preprint: He et al , 2022), using Scanpy's tl.score_genes function.…”

Section: Methodsmentioning

confidence: 99%

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SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling

et al. 2022

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The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor selfrenewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling

et al. 2022

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“…When considering distal epithelial cell types, T21 lungs showed an increased proportion of defined AT1 (Cluster 2) and AT2 (Cluster 6) cell populations, but a significant diminution in progenitor-like "transitional" AT1/AT2 cells (Cluster 4; p=0.01). These proportionality differences suggest precocious differentiation of epithelial cells occurs in T21 lungs 11 .…”

Section: Precocious Epithelial Cell Differentiation In Prenatal T21 L...mentioning

confidence: 96%

A Trisomy 21 Lung Cell Atlas

Bhattacharya

Cherry

Deutsch

et al. 2023

Preprint

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Trisomy 21 (T21), resulting in Down Syndrome (DS), is the most prevalent chromosomal abnormality worldwide. While pulmonary disease is a major cause of morbidity and mortality in DS, the ontogeny of pulmonary complications remains poorly understood. We recently demonstrated that T21 lung anomalies, including airway branching and vascular lymphatic abnormalities, are initiated in utero. Here, we aimed to describe molecular changes at the single cell level in prenatal T21 lungs. Our results demonstrate differences in the proportion of cell populations and detail changes in gene expression at the time of initiation of histopathological abnormalities. Notably, we identify shifts in the distribution of alveolar epithelial progenitors, widespread induction of key extracellular matrix molecules in mesenchymal cells and hyper-activation of IFN signaling in endothelial cells. This single cell atlas of T21 lungs greatly expands our understanding of antecedents to pulmonary complications and should facilitate efforts to mitigate respiratory disease in DS.

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“…Identification of human-specific progenitor cells and suitable environmental conditions allowed for generation of self-renewing human embryonic lung organoids. Dr Nikolić showed recent data emphasising the importance of cell–cell interactions during development,71 giving examples of mesenchymal-epithelial cell interactions directing airway zonation and fetal lung-derived immune cells influencing epithelial cell differentiation.…”

Section: Joint Bts/balr Symposium Part 2: Seven Ages Of the Lung: Wea...mentioning

confidence: 99%

Review of the British Thoracic Society Winter Meeting 23 November 2022 23–25 November 2022

Ward

Jha

Daynes

et al. 2023

Thorax

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The British Thoracic Society Winter Meeting at the QEII Centre in London provided the first opportunity for the respiratory community to meet and disseminate research findings face to face since the start of the COVID-19 pandemic. World-leading researchers from the UK and abroad presented their latest findings across a range of respiratory diseases. This article aims to represent the range of the conference and as such is written from the perspective of a basic scientist, a physiotherapist and two doctors. The authors reviewed showcase sessions plus a selection of symposia based on their personal highlights. Content ranged from exciting new developments in basic science to new and unpublished results from clinical trials, delivered by leading scientists from their fields including former deputy chief medical officer Professor Sir Jonathan Van-Tam and former WHO chief scientist Dr Soumya Swaminathan.

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A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

Cited by 103 publications

References 98 publications

SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling

SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling

A Trisomy 21 Lung Cell Atlas

Review of the British Thoracic Society Winter Meeting 23 November 2022 23–25 November 2022

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