Submucosal glands in the cartilaginous airways are thought to play important roles in protecting the human lung from infection by secreting antibacterial factors and controlling the composition and viscosity of fluid in the airways. In diseases such as cystic fibrosis (CF), asthma, and chronic bronchitis, Submucosal glands expand in mass (hypertrophy) and/or abundance (hyperplasia), leading to excessive and abnormal mucus production. Genetic defects in serous cells of submucosal glands have also been hypothesized to be a contributing factor in lung disease in CF. In addition to playing a role in innate immunity of the airways, submucosal gland ducts have also recently been recognized as a potential protective niche for proximal airway stem cells. During the previous two funding cycles of this grant, our laboratory has focused on elucidating the mechanisms of submucosal gland development from proximal airway progenitors using human, ferret, and mouse model systems. The goal of these studies has been to better characterize the phenotype of glandular progenitor cells by understanding the transcriptional pathways that control the growth of glands in the airway during normal development. Since submucosal gland progenitors also appear to have the capacity to contribute to surface airway epithelial cell renewal, the biology of stem cells in both submucosal gland and surface epithelial compartments may be closely linked. We have previously demonstrated that a transcription factor, lymphoid enhancing factor-1 (Lef-1), is induced during the initial stages of airway progenitor/stem cell commitment to form submucosal glands and is absolutely required for glands to develop in the airway. More recently, we have begun to dissect the regulatory pathways that control transcriptional activation of the Lef-1 promoter in cell line models and glandular progenitors in transgenic mice. We have found that Wnt/(3-catenin pathways appear to play a critical role in regulating the Lef-1 promoter through a set of related HMG-box transcription factors (TCP and Sox). This proposal will use in vitro polarized airway models, exvivo xenograft airway models, and genetic mouse models to study how Wnts, Noggin, and BMPs coordinate TCF/Sox regulation of the Lef-1 promoter during submucosal gland morphogenesis. Based on the inhibitory and enhancer functions of an identified Wnt-responsive element in the Lef-1 promoter, we hypothesize that Lef-1 regulation in glandular progenitors is controlled by both inhibitory (Sox and BMPs) and inductive (Wnt, TCF, and Noggin) signals. These hypotheses will be tested using viral vector systems and knockout mouse models capable of modulating the abundance of both extrinsic secreted factors and intrinsic transcription factors important for maintaining progenitor/stem cell phenotype and/or commitment to form glands. Lastly, this proposal will also attempt to evaluate whether TCF/Lef-1 pathways play a role in maintaining and/or mobilizing glandular duct stem cell niches for surface airway epithelial renewal following injury. Ultimately, this project will increase our understanding of stem cell phenotypes in the airway that have multipotent capacity for submucosal gland development and potentially also surface airway epithelial renewal. An increased understanding of submucosal gland morphogenesis may aid in the development of new therapeutic approaches to treat submucosal gland hyperplasia and hypertrophy in hypersecretory lung diseases. Furthermore, a greater knowledge of stem cell biology in the airway will greatly benefit the development genetic-based therapies for inhibited disease such as CF.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Eggerman, Thomas L
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University of Iowa
Anatomy/Cell Biology
Schools of Medicine
Iowa City
United States
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Lynch, Thomas J; Anderson, Preston J; Rotti, Pavana G et al. (2018) Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell 22:653-667.e5
Anderson, Preston J; Lynch, Thomas J; Engelhardt, John F (2017) Multipotent Myoepithelial Progenitor Cells Are Born Early during Airway Submucosal Gland Development. Am J Respir Cell Mol Biol 56:716-726
Lynch, Thomas J; Anderson, Preston J; Xie, Weiliang et al. (2016) Wnt Signaling Regulates Airway Epithelial Stem Cells in Adult Murine Submucosal Glands. Stem Cells 34:2758-2771
Evans, T Idil Apak; Joo, Nam Soo; Keiser, Nicholas W et al. (2016) Glandular Proteome Identifies Antiprotease Cystatin C as a Critical Modulator of Airway Hydration and Clearance. Am J Respir Cell Mol Biol 54:469-81
Mou, Hongmei; Vinarsky, Vladimir; Tata, Purushothama Rao et al. (2016) Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell Stem Cell 19:217-231
Joo, Nam Soo; Evans, Idil Apak T; Cho, Hyung-Ju et al. (2015) Proteomic analysis of pure human airway gland mucus reveals a large component of protective proteins. PLoS One 10:e0116756
Keiser, Nicholas W; Birket, Susan E; Evans, Idil A et al. (2015) Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs. Am J Respir Cell Mol Biol 52:683-94
Sun, Xingshen; Olivier, Alicia K; Liang, Bo et al. (2014) Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets. Am J Respir Cell Mol Biol 50:502-12
Xie, Weiliang; Lynch, Thomas J; Liu, Xiaoming et al. (2014) Sox2 modulates Lef-1 expression during airway submucosal gland development. Am J Physiol Lung Cell Mol Physiol 306:L645-60
Peng, Xinxia; Alföldi, Jessica; Gori, Kevin et al. (2014) The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease. Nat Biotechnol 32:1250-5

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