title: Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations.
abstract: Following injury, stem cells restore normal tissue architecture by producing the proper number and proportions of differentiated cells. Current models of airway epithelial regeneration propose that distinct cytokeratin 8-expressing progenitor cells, arising from p63(+) basal stem cells, subsequently differentiate into secretory and ciliated cell lineages. We now show that immediately following injury, discrete subpopulations of p63(+) airway basal stem/progenitor cells themselves express Notch pathway components associated with either secretory or ciliated cell fate commitment. One basal cell population displays intracellular Notch2 activation and directly generates secretory cells; the other expresses c-myb and directly yields ciliated cells. Furthermore, disrupting Notch ligand activity within the basal cell population at large disrupts the normal pattern of lineage segregation. These non-cell-autonomous effects demonstrate that effective airway epithelial regeneration requires intercellular communication within the broader basal stem/progenitor cell population. These findings have broad implications for understanding epithelial regeneration and stem cell heterogeneity.
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Ana
authors: A
authors: Pardo-Saganta
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Brandon M
authors: BM
authors: Law
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Purushothama Rao
authors: PR
authors: Tata
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Jorge
authors: J
authors: Villoria
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Borja
authors: B
authors: Saez
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Hongmei
authors: H
authors: Mou
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors: Rui
authors: R
authors: Zhao
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: jrajagopal@mgh.harvard.edu.
authors: Jayaraj
authors: J
authors: Rajagopal
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002713:Chlorine; D004318:Doxycycline; D051379:Mice; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D013458:Sulfur Dioxide; D014947:Wounds and Injuries / Q000139:chemically induced / Q000628:therapy*
chemical_list: D013458:Sulfur Dioxide; D002713:Chlorine; D004318:Doxycycline