Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells

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.

miR-484: A Possible Indicator of Drug-Induced Pulmonary Fibrosis

“…To the best of our knowledge, our study is the first to provide evidence concerning the relationship between miR-484 and drug-induced EMT in the lungs. Although several research groups, including our own, have elucidated bleomycin-induced EMT, different concentrations of bleomycin with a large range (0.4-120 µM) were used to induce EMT in those studies [14,[21][22][23][24][25][26]. For example, we used 60-µM bleomycin to induce EMT in A549 and A549/ABCA3 cells [14,24], while 0.4 µMbleomycin induced EMT-like phenotypical changes of RLE/Abca3 cells derived from rat normal alveolar epithelium [21].…”

Inhibition of CD44 suppresses the formation of fibrotic scar after spinal cord injury via the JAK2/STAT3 signaling pathway

“…Numerous studies have reported that CD44, a type-I transmembrane glycoprotein, participates in inflammation and tissue fibrosis. 15 , 16 , 17 , 18 CD44 is widely expressed in most vertebrate cells, including fibroblasts. 19 , 20 , 21 As a cell adhesion molecule, CD44 plays a role in cell-cell and cell-matrix interactions 22 in various pathological processes, such as lymphocyte infiltration, 23 , 24 wound healing, and scar formation.…”

Pharmacological and Nutraceutical Activation of Rejuvenation, Geroprotection and Cytoprotection: Proofs of Concept

“…Such an epithelial–mesenchymal transdifferentiation leads to lung fibrosis. The proof of concept was achieved in bleomycin-treated chimeric mice injected with CD44 knockout mesenchymal cells [ 38 ].…”