Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium

Lynch, Thomas J.; Anderson, Preston J.; Rotti, Pavana G.; Tyler, Scott R.; Crooke, Adrianne K.; Choi, Soon Ho; Montoro, Daniel T.; Silverman, Carolyn L.; Shahin, Weam; Zhao, Rui; Jensen-Cody, Chandler Walker; Adamcakova‐Dodd, Andrea; Evans, T. Idil Apak; Xie, Weiliang; Zhang, Yulong; Mou, Hongmei; Herring, B. Paul; Thorne, Peter S.; Rajagopal, Jayaraj; Yeaman, Charles; Parekh, Kalpaj R.; Engelhardt, John F.

doi:10.1016/j.stem.2018.04.007

Cited by 42 publications

(39 citation statements)

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“…The submucosal gland epithelium contains mucous- and serous-secreting cells, as well as myoepithelial basal cells. In mice, the submucosal myoepithelial basal cells function as stem cells for the submucosal gland itself and also as reserve stem cells that contribute to regeneration of the surface epithelium of the airways after severe injury ( Lynch et al, 2018 ; Tata et al, 2018a ). Interestingly, pig submucosal glands also contribute to the airway surface epithelium following injury, strongly suggesting that the situation in the human lung will be similar ( Tata et al, 2018a ).…”

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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“…In contrast, Wnt/b-catenin activation can also lead to loss of MCCs or Goblet cell hyperplasia (Hashimoto et al, 2012;Mucenski et al, 2005;Reynolds et al, 2008;Schmid et al, 2017). Additional effects for Wnt were proposed in submucosal glands, during regeneration and in regulating proliferation (Driskell et al, 2004;Hogan et al, 2014;Lynch et al, 2018;Pongracz and Stockley, 2006). Dysregulation of Wnt signaling is commonly observed in chronic lung diseases such as COPD and idiopathic pulmonary fibrosis (IPF) (Baarsma and Kö nigshoff, 2017;Pongracz and Stockley, 2006).…”

Section: Introductionmentioning

confidence: 99%

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia

et al. 2019

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SUMMARY Mucociliary epithelia provide a first line of defense against pathogens. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive, and studies yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway Basal cells, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in vertebrates. In multiciliated cells, Wnt is required for cilia formation during differentiation. In Basal cells, Wnt prevents specification of epithelial cell types by activating ΔN-TP63, a master transcription factor, which is necessary and sufficient to mediate the Wnt-induced inhibition of specification and is required to retain Basal cells during development. Chronic Wnt activation leads to remodeling and Basal cell hyperplasia, which are reversible in vivo and in vitro, suggesting Wnt inhibition as a treatment option in chronic lung diseases. Our work provides important insights into mucociliary signaling, development, and disease.

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“…Columnar epithelial cells from the pseudostratified regions demonstrate extensive plasticity in which they can dedifferentiate into basal cells (Tata and Rajagopal, 2017). Studies in the porcine model of CF suggest the importance of submucosal gland dysfunction in CF pathogenesis (Hoegger et al, 2014) and lineage tracing in mice illustrates a key role for gland myoepithelial cells in repair (Lynch et al, 2018; Tata et al, 2018). The ability to access, propagate and correct human gland myoepithelial cells, and their ultimate return to gland tubular and acinar niches will require more study.…”

Section: Stem Cells In the Conducting Airwaysmentioning

confidence: 99%

Challenges Facing Airway Epithelial Cell-Based Therapy for Cystic Fibrosis

Berical

Randell

et al. 2019

Front. Pharmacol.

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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the life-limiting hereditary disease, cystic fibrosis (CF). Decreased or absent functional CFTR protein in airway epithelial cells leads to abnormally viscous mucus and impaired mucociliary transport, resulting in bacterial infections and inflammation causing progressive lung damage. There are more than 2000 known variants in the CFTR gene. A subset of CF individuals with specific CFTR mutations qualify for pharmacotherapies of variable efficacy. These drugs, termed CFTR modulators, address key defects in protein folding, trafficking, abundance, and function at the apical cell membrane resulting from specific CFTR mutations. However, some CFTR mutations result in little or no CFTR mRNA or protein expression for which a pharmaceutical strategy is more challenging and remote. One approach to rescue CFTR function in the airway epithelium is to replace cells that carry a mutant CFTR sequence with cells that express a normal copy of the gene. Cell-based therapy theoretically has the potential to serve as a one-time cure for CF lung disease regardless of the causative CFTR mutation. In this review, we explore major challenges and recent progress toward this ambitious goal. The ideal therapeutic cell would: (1) be autologous to avoid the complications of rejection and immune-suppression; (2) be safely modified to express functional CFTR; (3) be expandable ex vivo to generate sufficient cell quantities to restore CFTR function; and (4) have the capacity to engraft, proliferate and persist long-term in recipient airways without complications. Herein, we explore human bronchial epithelial cells (HBECs) and induced pluripotent stem cells (iPSCs) as candidate cell therapies for CF and explore the challenges facing their delivery to the human airway.

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Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium

Cited by 42 publications

References 0 publications

Human lung development: recent progress and new challenges

Human lung development: recent progress and new challenges

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia

Challenges Facing Airway Epithelial Cell-Based Therapy for Cystic Fibrosis

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