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Journal Article Ppublish 61 citations

PubMed: 38693267 DOI: 10.1038/s41586-024-07377-1

Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.

Nature 629(8013):869-877

Authors: Brian Lin, Viral S Shah, Chaim Chernoff, Jiawei Sun, Gergana G Shipkovenska, Vladimir Vinarsky, Avinash Waghray, Jiajie Xu, Andrew D Leduc, Constantin A Hintschich, Manalee Vishnu Surve, Yanxin Xu, Diane E Capen, Jorge Villoria, Zhixun Dou, Lida P Hariri, Jayaraj Rajagopal

Affiliations

  • Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Harvard Stem Cell Institute, Cambridge, MA, USA.
  • Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
  • Department of Developmental, Molecular and Chemical Biology, School of Medicine, Tufts University, Boston, MA, USA.
  • Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Harvard Stem Cell Institute, Cambridge, MA, USA.
  • Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
  • Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Stem Cell Institute, Cambridge, MA, USA. Developmental and Regenerative Biology Program, Harvard, Cambridge, MA, USA.
  • Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Stem Cell Institute, Cambridge, MA, USA.
  • Department of Bioengineering, Northeastern University, Boston, MA, USA.
  • Department of Developmental, Molecular and Chemical Biology, School of Medicine, Tufts University, Boston, MA, USA.
  • Department of Otorhinolaryngology, Regensburg University Hospital, Regensburg, Germany.
  • Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
  • Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Harvard Stem Cell Institute, Cambridge, MA, USA.
  • Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
  • Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Developmental and Regenerative Biology Program, Harvard, Cambridge, MA, USA.

Abstract

Airway hillocks are stratified epithelial structures of unknown function. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.

MeSH

Cells, Microscopy, Electron, Scanning Transmission, Stem Cells, Metaplasia, Epithelium, Plastics

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