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

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

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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. Following severe injury to the surface airway epithelium (SAE), Wnt signals activate myoepithelial cells in the submucosal glands (SMGs) to function as reserve stem cells for multipotent basal cells in the SAE and other SMG cell types. Lef-1 activation induces the myoepithelial cell regenerative response and a basal cell-like phenotype.

Original languageEnglish (US)
Pages (from-to)653-667.e5
JournalCell Stem Cell
Volume22
Issue number5
DOIs
StatePublished - May 3 2018

Keywords

  • LEF1
  • airway basal cell
  • injury repair
  • lineage-trace
  • lymphoid enhancer-binding factor-1
  • multipotency
  • myoepithelial cell
  • plasticity

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Lynch, T. J., Anderson, P. J., Rotti, P. G., Tyler, S. R., Crooke, A. K., Choi, S. H., Montoro, D. T., Silverman, C. L., Shahin, W., Zhao, R., Jensen-Cody, C. W., Adamcakova-Dodd, A., Evans, T. I. A., Xie, W., Zhang, Y., Mou, H., Herring, B. P., Thorne, P. S., Rajagopal, J., ... Engelhardt, J. F. (2018). Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell, 22(5), 653-667.e5. https://doi.org/10.1016/j.stem.2018.03.017