FGFR2 is required for airway basal cell self-renewal and terminal differentiation

Balasooriya, Gayan I.; Goschorska, Maja; Piddini, Eugenia; Rawlins, Emma L.

doi:10.1242/dev.135681

Cited by 43 publications

(34 citation statements)

References 33 publications

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“…Following our experience with generating organoids from other adult human tissues Karthaus et al, 2014;Boj et al, 2015;Huch et al, 2015;van de Wetering et al, 2015) and recent developments in the field (Mou et al, 2016;Tadokoro et al, 2016;Balasooriya et al, 2017), we embedded isolated cells in basement membrane extract (BME) and activated/blocked signaling pathways important for airway epithelium (Table EV1). Following our experience with generating organoids from other adult human tissues Karthaus et al, 2014;Boj et al, 2015;Huch et al, 2015;van de Wetering et al, 2015) and recent developments in the field (Mou et al, 2016;Tadokoro et al, 2016;Balasooriya et al, 2017), we embedded isolated cells in basement membrane extract (BME) and activated/blocked signaling pathways important for airway epithelium (Table EV1).…”

Section: Generation and Characterization Of Human Airway Organoidsmentioning

confidence: 99%

“…We collected macroscopically inconspicuous lung tissue from nonsmall-cell lung cancer (NSCLC) patients undergoing medically indicated surgery and isolated epithelial cells through mechanical and enzymatic tissue disruption (see Materials and Methods). Following our experience with generating organoids from other adult human tissues Karthaus et al, 2014;Boj et al, 2015;Huch et al, 2015;van de Wetering et al, 2015) and recent developments in the field (Mou et al, 2016;Tadokoro et al, 2016;Balasooriya et al, 2017), we embedded isolated cells in basement membrane extract (BME) and activated/blocked signaling pathways important for airway epithelium (Table EV1). Under optimized conditions, 3D organoids formed within several days (94% success rate, n = 18).…”

Section: Generation and Characterization Of Human Airway Organoidsmentioning

confidence: 99%

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Long‐term expanding human airway organoids for disease modeling

et al. 2019

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Organoids are self‐organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long‐term‐expanding human airway organoids from broncho‐alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi‐ciliated cells, mucus‐producing secretory cells, and CC10‐secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non‐structural viral NS2 protein, and preferentially recruits neutrophils upon co‐culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

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Section: Generation and Characterization Of Human Airway Organoidsmentioning

confidence: 99%

Section: Generation and Characterization Of Human Airway Organoidsmentioning

confidence: 99%

Long‐term expanding human airway organoids for disease modeling

et al. 2019

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“…Interestingly, ubiquitous Fgf10 overexpression promotes basal cell lineage commitment and suppresses ciliated cell differentiation (Volckaert et al, 2013). Conversely, deletion of Fgf10 or its receptor Fgfr2 results in the loss of basal cells (Balasooriya et al, 2017;Volckaert et al, 2013). In addition, ubiquitous overexpression of the Wnt inhibitor Dkk1 at embryonic day (E) 10.5 but not E12.5 also leads to increased numbers of basal cells (Volckaert et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Wnt/Fgf crosstalk is required for the specification of basal cells in the mouse trachea

Hou

Sun

et al. 2019

Development

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Basal progenitor cells are crucial for the establishment and maintenance of the tracheal epithelium. However, it remains unclear how these progenitor cells are specified during foregut development.Here, we found that ablation of the Wnt chaperone protein Gpr177 (also known as Wntless) in mouse tracheal epithelium causes a significant reduction in the number of basal progenitor cells accompanied by cartilage loss in Shh-Cre;Gpr177 loxp/loxp mutants. Consistent with the association between cartilage and basal cell development, Nkx2.1 + p63 + basal cells are co-present with cartilage nodules in Shh-Cre;Ctnnb1 DM/loxp mutants, which maintain partial cellcell adhesion but not the transcription regulation function of β-catenin. More importantly, deletion of Ctnnb1 in the mesenchyme leads to the loss of basal cells and cartilage, concomitant with reduced transcript levels of Fgf10 in Dermo1-Cre;Ctnnb1 loxp/loxp mutants. Furthermore, deletion of Fgf receptor 2 (Fgfr2) in the epithelium also leads to significantly reduced numbers of basal cells, supporting the importance of Wnt/Fgf crosstalk in early tracheal development.

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“…In particular, epithelium-derived WNT ligands are emerging as key mediators activating the mesenchymal niche that in turn produces FGF10, leading to epithelial stem-cell activation and regeneration. This mechanism has been shown to be critical for activating at least two types of epithelial stem/progenitor cells in the lung: basal stem cells (Balasooriya et al, 2017;Volckaert et al, 2017) and club cells (Lee et al, 2017;Volckaert et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

A smooth muscle-like niche facilitates lung epithelial regeneration

Moiseenko

Vazquez‐Armendariz

Chu

et al. 2019

Preprint

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The mammalian lung is a highly complex organ due to its branched, tree-like structure and diverse cellular composition. Recent efforts using state-of-the-art genetic lineage tracing and single-cell transcriptomics have helped reduce this complexity and delineate the ancestry and fate of various cell subpopulations during organogenesis, homeostasis and repair after injury. However, mesenchymal cell heterogeneity and function in development and disease remain a longstanding issue in the lung field. In this study, we break down smooth muscle heterogeneity into the constituent subpopulations by combining in vivo lineage tracing, single-cell RNA sequencing and in vitro organoid cultures. We identify a repair-supportive mesenchymal cell (RSMC) population that is distinct from pre-existing airway smooth muscle cells (ASMC) and is critical for regenerating the conducting airway epithelium. Progenitors of RSMCs are intertwined with airway smooth muscle, undergo active WNT signaling, transiently acquire the expression of the smooth muscle marker ACTA2 in response to epithelial injury and are marked by PDGFRα expression. Our data simplify the cellular complexity of the peribronchiolar domain of the adult lung and represent a forward step towards unraveling the role of mesenchymal cell subpopulations in instructing epithelial behavior during repair processes.

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FGFR2 is required for airway basal cell self-renewal and terminal differentiation

Cited by 43 publications

References 33 publications

Long‐term expanding human airway organoids for disease modeling

Long‐term expanding human airway organoids for disease modeling

Wnt/Fgf crosstalk is required for the specification of basal cells in the mouse trachea

A smooth muscle-like niche facilitates lung epithelial regeneration

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