Browsing by Author "Shahin, Weam"

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    Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium
    (Elsevier, 2018-05-03) Lynch, Thomas J.; Anderson, Preston J.; Rotti, Pavana G.; Tyler, Scott R.; Crooke, Adrianne K.; Choi, Soon H.; Montoro, Daniel T.; Silverman, Carolyn L.; Shahin, Weam; Zhao, Rui; Jensen-Cody, Chandler; 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.; Cellular and Integrative Physiology, School of Medicine
    The mouse trachea is thought to contain two distinct stem cell compartments that contribute to airway repair-basal cells in the surface airway epithelium (SAE) and an unknown submucosal gland (SMG) cell type. Whether a lineage relationship exists between these two stem cell compartments remains unclear. Using lineage tracing of glandular myoepithelial cells (MECs), we demonstrate that MECs can give rise to seven cell types of the SAE and SMGs following severe airway injury. MECs progressively adopted a basal cell phenotype on the SAE and established lasting progenitors capable of further regeneration following reinjury. MECs activate Wnt-regulated transcription factors (Lef-1/TCF7) following injury and Lef-1 induction in cultured MECs promoted transition to a basal cell phenotype. Surprisingly, dose-dependent MEC conditional activation of Lef-1 in vivo promoted self-limited airway regeneration in the absence of injury. Thus, modulating the Lef-1 transcriptional program in MEC-derived progenitors may have regenerative medicine applications for lung diseases.
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    Transgenic ferret models define pulmonary ionocyte diversity and function
    (Springer Nature, 2023) Yuan, Feng; Gasser, Grace N.; Lemire, Evan; Montoro, Daniel T.; Jagadeesh, Karthik; Zhang, Yan; Duan, Yifan; Levlev, Vitaly; Wells, Kristen L.; Rotti, Pavana G.; Shahin, Weam; Winter, Michael; Rosen, Bradley H.; Evans, Idil; Cai, Qian; Yu, Miao; Walsh, Susan A.; Acevedo, Michael R.; Pandya, Darpan N.; Akurathi, Vamsidhar; Dick, David W.; Wadas, Thaddeus J.; Joo, Nam Soo; Wine, Jeffrey J.; Birket, Susan; Fernandez, Courtney M.; Leung, Hui Min; Tearney, Guillermo J.; Verkman, Alan S.; Haggie, Peter M.; Scott, Kathleen; Bartels, Douglas; Meyerholz, David K.; Rowe, Steven M.; Liu, Xiaoming; Yan, Ziying; Haber, Adam L.; Sun, Xingshen; Engelhardt, John F.; Medicine, School of Medicine
    Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.