Increased regeneration following stress-induced lung injury in bleomycin-treated chimeric mice with cd44 knockout mesenchymal cells

Dmytro Petukhov, Mark Richter-Dayan, Zvi Fridlender, Raphael Breuer, Shulamit B. Wallach-Dayan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

CD44, an adhesion-molecule promoting cell-migration, is shown here to increase in stress conditions following bleomycin-induced apoptosis in alveolar epithelial cells (AECs), a main target of lung injury. In vivo, it inhibits tissue regeneration and leads to fibrosis. We show that some AECs survive by the ataxia-telangiectasia mutated kinase/ATM pathway, and undergo a CD44-mediated epithelial-mesenchymal transdifferentiation (EMT) with migratory capacities in vitro, and in vivo. We assessed apoptosis vs. proliferation of AECs following bleomycin, ATM/P53 signaling pathway in AECs, and CD44 involvement in EMT, cell motility and tissue regeneration in vitro and in vivo. Expression of survival genes, CD44, and ATM/p53 pathway was elevated in AECs surviving bleomycin injury, as were the markers of EMT (downregulation of E-cadherin, upregulation of N-cadherin and vimentin, nuclear translocation of β-catenin). Inhibition of CD44 decreased AECs transdifferentiation. Bleomycin-treated chimeric CD44KO-mice had decreased EMT markers, ATM, and mesenchymal cells (α-SMA+) accumulation in lung, increased surfactant-b, diminished lung mesenchymal cell motility, and increased lung tissue regenerative capacity following bleomycin injury, as indicated by lung collagen content and semiquantitave morphological index scoring. Thus, AECs surviving lung injury are plastic and undergo ATM-mediated, CD44-dependent transdifferentiation, preventing tissue regeneration and promoting fibrosis. Synthetic or natural compounds that downregulate CD44 may improve tissue regeneration following injury.

Original languageAmerican English
Article number1211
JournalCells
Volume8
Issue number10
DOIs
StatePublished - Oct 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 by the authors.

Keywords

  • ATM
  • Bleomycin
  • CD44
  • Cell-survival
  • Epithelial-mesenchymal transition
  • Fibrosis
  • Oxidative stress
  • Regeneration

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