PTEN inhibition improves wound healing in lung epithelia through changes in cellular mechanics that enhance migration.
The phosphoinositide-3 kinase/Akt pathway is a vital survival axis in lung epithelia. We previously reported that inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major suppressor of this pathway, results in enhanced wound repair following injury. However, the precise cellular and biomechanical mechanisms responsible for increased wound repair during PTEN inhibition are not yet well established. Using primary human lung epithelia and a related lung epithelial cell line, we first determined whether changes in migration or proliferation account for wound closure. Strikingly, we observed that cell migration accounts for the majority of wound recovery following PTEN inhibition in conjunction with activation of the Akt and ERK signaling pathways. We then used fluorescence and atomic force microscopy to investigate how PTEN inhibition alters the cytoskeletal and mechanical properties of the epithelial cell. PTEN inhibition did not significantly alter cytoskeletal structure but did result in large spatial variations in cell stiffness and in particular a decrease in cell stiffness near the wound edge. Biomechanical changes, as well as migration rates, were mediated by both the Akt and ERK pathways. Our results indicate that PTEN inhibition rapidly alters biochemical signaling events that in turn provoke alterations in biomechanical properties that enhance cell migration. Specifically, the reduced stiffness of PTEN-inhibited cells promotes larger deformations, resulting in a more migratory phenotype. We therefore conclude that increased wound closure consequent to PTEN inhibition occurs through enhancement of cell migration that is due to specific changes in the biomechanical properties of the cell.
Department of Biomedical Engineering, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Cosmin
C
Mihai
Shengying
S
Bao
Ju-Ping
JP
Lai
Samir N
SN
Ghadiali
Daren L
DL
Knoell
D008841:Actin Cytoskeleton / Q000378:metabolism; D001696:Biomechanical Phenomena; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology*; D055370:Lung Injury / Q000188:drug therapy / Q000517:prevention & control; D020935:MAP Kinase Signaling System; D018625:Microscopy, Atomic Force; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017968:Vanadium Compounds / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
D017968:Vanadium Compounds; C472777:bisperoxovanadium; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human