Uroplakin 3a+ Cells Are a Distinctive Population of Epithelial Progenitors that Contribute to Airway Maintenance and Post-injury Repair

Guha, Arjun; Deshpande, Aditya; Jain, Aradhya; Sebastiani, Paola; Cardoso, Wellington V.

doi:10.1016/j.celrep.2017.03.051

Cited by 92 publications

(83 citation statements)

References 26 publications

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“…Basal cells are present throughout human conducting airways, but are confined to the trachea and primary bronchi of mice (Boers et al, 1998; Nakajima et al, 1998). In mice, it is clear that the dome-shaped club cells in the bronchioles act as stem cells for day-to-day airway epithelial maintenance and repair (Giangreco et al, 2009, 2002; Hong et al, 2001; Rawlins et al, 2009b) and can even contribute to the alveolar epithelium following injury (Guha et al, 2017). In contrast, club cells within the pseudostratified mouse trachea are progenitors that do not exhibit long-term self-renewal, but do divide for a limited time and can produce new ciliated cells (Rawlins et al, 2009b; Watson et al, 2015).…”

Section: An Introduction To Human Lung Developmentmentioning

confidence: 99%

Human lung development: recent progress and new challenges

2018

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Recent studies have revealed biologically significant differences between human and mouse lung development, and have reported new in vitro systems that allow experimental manipulation of human lung models. At the same time, emerging clinical data suggest that the origins of some adult lung diseases are found in embryonic development and childhood. The convergence of these research themes has fuelled a resurgence of interest in human lung developmental biology. In this Review, we discuss our current understanding of human lung development, which has been profoundly influenced by studies in mice and, more recently, by experiments using in vitro human lung developmental models and RNA sequencing of human foetal lung tissue. Together, these approaches are helping to shed light on the mechanisms underlying human lung development and disease, and may help pave the way for new therapies.

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Section: An Introduction To Human Lung Developmentmentioning

confidence: 99%

Human lung development: recent progress and new challenges

2018

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“…During embryonic development, cells surrounding PNECs, i.e., presumptive CLCs, remain undifferentiated [ 30 ]. CLCs/vCE cells appear to be resistant to naphthalene ablation because, unlike CCs, they do not express the cytochrome P450 2F2 isozyme [ 12 , 43 , 44 ]. It has been reported that CLCs in postnatal lungs show the capacity to regenerate both CCs and ciliated cells [ 45 , 46 ], but that severe epithelial injury is required to activate the stem cell niche for repair [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Selective activation and proliferation of a quiescent stem cell population in the neuroepithelial body microenvironment

et al. 2018

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BackgroundThe microenvironment (ME) of neuroepithelial bodies (NEBs) harbors densely innervated groups of pulmonary neuroendocrine cells that are covered by Clara-like cells (CLCs) and is believed to be important during development and for adult airway epithelial repair after severe injury. Yet, little is known about its potential stem cell characteristics in healthy postnatal lungs.MethodsTransient mild lung inflammation was induced in mice via a single low-dose intratracheal instillation of lipopolysaccharide (LPS). Bronchoalveolar lavage fluid (BALF), collected 16 h after LPS instillation, was used to challenge the NEB ME in ex vivo lung slices of control mice. Proliferating cells in the NEB ME were identified and quantified following simultaneous LPS instillation and BrdU injection.ResultsThe applied LPS protocol induced very mild and transient lung injury. Challenge of lung slices with BALF of LPS-treated mice resulted in selective Ca2+-mediated activation of CLCs in the NEB ME of control mice. Forty-eight hours after LPS challenge, a remarkably selective and significant increase in the number of divided (BrdU-labeled) cells surrounding NEBs was observed in lung sections of LPS-challenged mice. Proliferating cells were identified as CLCs.ConclusionsA highly reproducible and minimally invasive lung inflammation model was validated for inducing selective activation of a quiescent stem cell population in the NEB ME. The model creates new opportunities for unraveling the cellular mechanisms/pathways regulating silencing, activation, proliferation and differentiation of this unique postnatal airway epithelial stem cell population.

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“…8,10,11 Most recently, Upk3a has also been proposed to identify a rare subset of club cells with differentiation potentials. 12 In alveoli, type II cells (AEC2) act as stem cells to produce both type I and II alveolar cells. 13,14 The BMP family members play key roles in lung development and homeostasis.…”

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confidence: 99%

The noncanonical BMP signaling pathway plays an important role in club cell regeneration

Shafiquzzaman

Biswas

et al. 2019

Stem Cells

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The bronchiole is a major site for the development of several life‐threatening disorders, including chronic obstructive pulmonary disease and lung adenocarcinomas. The bronchiolar epithelium is composed of club cells and ciliated epithelial cells, with club cells serving as progenitor cells. Presently, the identity of the cells involved in regeneration of bronchiolar epithelium and the underlying mechanisms remain incompletely understood. Here, we show that Prrx1, a homeobox transcription factor, can mark club cells in adult mice during homeostasis and regeneration. We further show that the noncanonical signaling pathway of BMPs, BMPR1A‐Tak1‐p38MAPK, plays a critical role in club cell regeneration. Ablation of Bmpr1a, Tak1, or Mapk14 (encoding p38α) in Prrx1+ club cells caused minimal effect on bronchiolar epithelium homeostasis, yet it resulted in severe defects in club cell regeneration and bronchiole repair in adult mice. We further show that this pathway supports proliferation and expansion of the regenerating club cells. Our findings thus identify a marker for club cells and reveal a critical role for the BMP noncanonical pathway in club cell regeneration.

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Uroplakin 3a+ Cells Are a Distinctive Population of Epithelial Progenitors that Contribute to Airway Maintenance and Post-injury Repair

Cited by 92 publications

References 26 publications

Human lung development: recent progress and new challenges

Human lung development: recent progress and new challenges

Selective activation and proliferation of a quiescent stem cell population in the neuroepithelial body microenvironment

The noncanonical BMP signaling pathway plays an important role in club cell regeneration

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