Distinct airway progenitor cells drive epithelial heterogeneity in the developing human lung

Conchola, Ansley S.; Fum, Tristan; Xiao, Zhiwei; Hsu, Peggy P.; Hein, Renee; Miller, Alyssa J.; Tsai, Yu-Hwai; Wu, Angeline; Kaur, Kamika; Holloway, Emily M.; Anand, Adarsh; Murthy, Preetish Kadur Lakshminarasimha; Glass, Ian S.; Tata, Purushothama Rao; Spence, Jason R.

doi:10.1101/2022.06.13.495813

Cited by 4 publications

(2 citation statements)

References 76 publications

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“…Perhaps in the setting of rare human genetic disorders characterized by an excess of NE cells, such as NEHI (Neuroendocrine hyperplasia of infancy) 56 , TIP cells can be pathologically diverted to produce excess NE cells. Alternatively, bronchial solitary NE cells may arise from a separate distinct rare cell progenitor population, as seen in the developing human lower airway 57 or could be sourced directly from basal cells as we have previously shown 56 .…”

Section: Discussionmentioning

confidence: 99%

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

Waghray,

Monga,

Lin

et al. 2023

Preprint

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The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendantsin vitro, resulting in the differentiation of mature tuft cells at the expense of ionocytes. Consistent with this model of mature tuft cell differentiation, we identify mature tuft cells in a patient who died from an asthma flare. Overall, our findings suggest that the immune signaling pathways active in asthma and CF may skew the composition of disease-relevant rare cells and illustrate how deep atlases are required for identifying physiologically-relevant scarce cell populations.

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Section: Discussionmentioning

confidence: 99%

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

Waghray,

Monga,

Lin

et al. 2023

Preprint

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“…To further characterize the intermediate cell state observed in Gramd2:KRAS G12D -initiated LUAD, we examined the profile of an additional marker of lung epithelial transitional cell states, secretoglobin 3a2 (SCGB3A2), which has been shown to generate multiple distal lung lineages in response to cellular damage and/or stress. 48,49 SCGB3A2 was also associated with KRT8 + expression in response to alveolar stress and injury resolution. 11 Scgb3a2 was elevated in LUAD-associated ICs (Figure 7A), but the expression of Scgb3a2 was elevated in Gramd2:KRAS G12D relative to expression in Sftpc:KRAS G12D LUAD array spots.…”

Section: Scgb3a2 Is Associated Specifically With At1-derived Luadmentioning

confidence: 93%

Alveolar Type I Cells Can Give Rise to Kras-Induced Lung Adenocarcinoma

Yang

Flodby

et al. 2023

Preprint

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Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis

Ikonomou

Yampolskaya

Mehta

2023

Advances in Experimental Medicine and Biology

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Transient, tissue-specific, embryonic progenitors are important cell populations in vertebrate development. In the course of respiratory system development, multipotent mesenchymal and epithelial progenitors drive the diversification of fates that results to the plethora of cell types that compose the airways and alveolar space of the adult lungs. Use of mouse genetic models, including lineage tracing and loss-of-function studies, has elucidated signaling pathways that guide proliferation and differentiation of embryonic lung progenitors as well as transcription factors that underlie lung progenitor identity. Furthermore, pluripotent stem cell-derived and ex vivo expanded respiratory progenitors offer novel, tractable, high-fidelity systems that allow for mechanistic studies of cell fate decisions and developmental processes. As our understanding of embryonic progenitor biology deepens, we move closer to the goal of in vitro lung organogenesis and resulting applications in developmental biology and medicine.

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Distinct airway progenitor cells drive epithelial heterogeneity in the developing human lung

Cited by 4 publications

References 76 publications

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

Alveolar Type I Cells Can Give Rise to Kras-Induced Lung Adenocarcinoma

Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis

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