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Airway hillocks are injury-resistant reservoirs of unique plastic stem cells – Nature

  • Montoro, D. T. et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560, 319–324 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lancillotti, F., Darwiche, N., Celli, G. & De Luca, L. M. Retinoid status and the control of keratin expression and adhesion during the histogenesis of squamous metaplasia of tracheal epithelium. Cancer Res. 52, 6144–6152 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • Chopra, D. P. Retinoid reversal of squamous metaplasia in organ cultures of tracheas derived from hamsters fed on vitamin A-deficient diet. Eur. J. Cancer Clin. Oncol. 19, 847–857 (1983).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Peter, M. et al. Transgenic mouse models enabling photolabeling of individual neurons in vivo. PLoS ONE 8, e62132 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Feldman, M. B., Wood, M., Lapey, A. & Mou, H. SMAD signaling restricts mucous cell differentiation in human airway epithelium. Am. J. Respir. Cell Mol. Biol. 61, 322–331 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tata, P. R. et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218–223 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Watson, J. K. et al. Clonal dynamics reveal two distinct populations of basal cells in slow-turnover airway epithelium. Cell Rep. 12, 90–101 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tadokoro, T. et al. Dorso-ventral heterogeneity in tracheal basal stem cells. Biol. Open 10, bio058676 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maclean, H. & Griffiths, W. J. The factors influencing the concentration of hydrochloric acid during gastric digestion. J. Physiol. 65, 63–76 (1928).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garner, J. L. et al. A prospective safety and feasibility study of metered cryospray for patients with chronic bronchitis in COPD. Eur. Respir. J. 56, 2000556 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DiBardino, D. M., Lanfranco, A. R. & Haas, A. R. Bronchoscopic cryotherapy. Clinical applications of the cryoprobe, cryospray, and cryoadhesion. Ann. Am. Thorac. Soc. 13, 1405–1415 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Tata, A. et al. Myoepithelial cells of submucosal glands can function as reserve stem cells to regenerate airways after injury. Cell Stem Cell 22, 668–683.e6 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lynch, T. J. et al. Submucosal gland myoepithelial cells are reserve stem cells that can regenerate mouse tracheal epithelium. Cell Stem Cell 22, 653–667.e5 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Isoherranen, N. & Zhong, G. Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases. Pharmacol. Ther. 204, 107400 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rajaii, F., Bitzer, Z. T., Xu, Q. & Sockanathan, S. Expression of the dominant negative retinoid receptor, RAR403, alters telencephalic progenitor proliferation, survival, and cell fate specification. Dev. Biol. 316, 371–382 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Srinivasan, B. et al. TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 20, 107–126 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nettesheim, P. et al. Pathways of differentiation of airway epithelial cells. Environ. Health Perspect. 85, 317–329 (1990).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. Human airway basal cells undergo reversible squamous differentiation and reshape innate immunity. Am. J. Respir. Cell Mol. Biol. https://doi.org/10.1165/rcmb.2022-0299OC (2023).

  • Deprez, M. et al. A single-cell atlas of the human healthy airways. Am. J. Respir. Crit. Care Med. 202, 1636–1645 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kersten, E. T. G. et al. Childhood-onset asthma is characterized by airway epithelial hillock-to-squamous differentiation in early life. Preprint at bioRxiv https://doi.org/10.1101/2023.07.31.549680 (2023).

  • Yoshida, M. et al. Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature 602, 321–327 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vieira Braga, F. A. et al. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat. Med. 25, 1153–1163 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alladina, J. et al. A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma. Sci. Immunol. 8, eabq6352 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nakamura, R. et al. A novel method for live imaging of human airway cilia using wheat germ agglutinin. Sci. Rep. 10, 14417 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sikkema, L. et al. An integrated cell atlas of the lung in health and disease. Nat. Med. 29, 1563–1577 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, T.-H. et al. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506, 511–515 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stange, D. E. et al. Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell 155, 357–368 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, Y. et al. Airway basal cells show regionally distinct potential to undergo metaplastic differentiation. eLife 11, e80083 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aros, C. J. et al. Distinct spatiotemporally dynamic Wnt-secreting niches regulate proximal airway regeneration and aging. Cell Stem Cell 27, 413–429.e4 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oliveira, M. J. R. et al. Zonation of ciliated cells on the epithelium of the rat trachea. Lung https://doi.org/10.1007/s00408-003-1030-1 (2003).

  • Borthwick, D. W., Shahbazian, M., Todd Krantz, Q., Dorin, J. R. & Randell, S. H. Evidence for stem-cell niches in the tracheal epithelium. Am. J. Respir. Cell Mol. https://doi.org/10.1165/ajrcmb.24.6.4217 (2001).

  • Hong, K. U., Reynolds, S. D., Watkins, S., Fuchs, E. & Stripp, B. R. In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L643–L649 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tilston-Lunel, A. et al. Aberrant epithelial polarity cues drive the development of precancerous airway lesions. Proc. Natl Acad. Sci. USA 118, e2019282118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Szymaniak, A. D., Mahoney, J. E., Cardoso, W. V. & Varelas, X. Crumbs3-mediated polarity directs airway epithelial cell fate through the Hippo pathway effector Yap. Dev. Cell 34, 283–296 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumar, P. A. et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147, 525–538 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rao, W. et al. Regenerative metaplastic clones in COPD lung drive inflammation and fibrosis. Cell https://doi.org/10.1016/j.cell.2020.03.047 (2020).

  • Taylor, M. S. et al. Delayed alveolar epithelialization: a distinct pathology in diffuse acute lung injury. Am. J. Respir. Crit. Care Med. 197, 522–524 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taylor, M. S. et al. A conserved distal lung regenerative pathway in acute lung injury. Am. J. Pathol. 188, 1149–1160 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cassandras, M. et al. Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung. Nat. Cell Biol. 22, 1295–1306 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, S. et al. Inflammatory activity of epithelial stem cell variants from cystic fibrosis lungs is not resolved by CFTR modulators. Am. J. Respir. Crit. Care Med. 208, 930–943 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vaughan, A. E. et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517, 621–625 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kathiriya, J. J. et al. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells. Nat. Cell Biol. 24, 10–23 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ray, S. et al. Rare SOX2+ airway progenitor cells generate KRT5+ cells that repopulate damaged alveolar parenchyma following influenza virus infection. Stem Cell Rep. 7, 817–825 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Planer, J. D. & Morrisey, E. E. After the storm: regeneration, repair, and reestablishment of homeostasis between the alveolar epithelium and innate immune system following viral lung injury. Annu. Rev. Pathol. 18, 337–359 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Rawlins, E. L. et al. The role of Scgb1a1 Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell https://doi.org/10.1016/j.stem.2009.04.002 (2009).

  • Rawlins, E. L. & Hogan, B. L. M. Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L231–L234 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. A transgenic FOXJ1-Cre system for gene inactivation in ciliated epithelial cells. Am. J. Respir. Cell Mol. Biol. 36, 515–519 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pontes-Quero, S. et al. Dual ifgMosaic: a versatile method for multispectral and combinatorial mosaic gene-function analysis. Cell 170, 800–814.e18 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, Z. et al. Hair follicle stem cells regulate retinoid metabolism to maintain the self-renewal niche for melanocyte stem cells. eLife 9, e52712 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics https://doi.org/10.1093/bioinformatics/bts635 (2013).

  • Trapnell, C. et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562–578 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e29 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Levardon, H., Yonker, L. M., Hurley, B. P. & Mou, H. Expansion of airway basal cells and generation of polarized epithelium. Bio Protoc. 8, e2877 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mou, H. et al. Dual SMAD signaling inhibition enables long-term expansion of diverse epithelial basal cells. Cell Stem Cell 19, 217–231 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, R. et al. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev. Cell 30, 151–165 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pardo-Saganta, A. et al. Parent stem cells can serve as niches for their daughter cells. Nature 523, 597–601 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shah, V. S. et al. Autofluorescence imaging permits label-free cell type assignment and reveals the dynamic formation of airway secretory cell associated antigen passages (SAPs). eLife 12, e84375 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Salic, A. & Mitchison, T. J. A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc. Natl Acad. Sci. USA 105, 2415–2420 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, B., Shah, V. & Rajagopal, J. Human airway wholemounts. Harvard Dataverse https://doi.org/10.7910/DVN/6JDXOP (2024).