Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.
Wound healing is essential for maintaining the integrity of multicellular organisms. In every species studied, disruption of an epithelial layer instantaneously generates endogenous electric fields, which have been proposed to be important in wound healing. The identity of signalling pathways that guide both cell migration to electric cues and electric-field-induced wound healing have not been elucidated at a genetic level. Here we show that electric fields, of a strength equal to those detected endogenously, direct cell migration during wound healing as a prime directional cue. Manipulation of endogenous wound electric fields affects wound healing in vivo. Electric stimulation triggers activation of Src and inositol-phospholipid signalling, which polarizes in the direction of cell migration. Notably, genetic disruption of phosphatidylinositol-3-OH kinase-gamma (PI(3)Kgamma) decreases electric-field-induced signalling and abolishes directed movements of healing epithelium in response to electric signals. Deletion of the tumour suppressor phosphatase and tensin homolog (PTEN) enhances signalling and electrotactic responses. These data identify genes essential for electrical-signal-induced wound healing and show that PI(3)Kgamma and PTEN control electrotaxis.
Zhao
Min
M
School of Medical Sciences and Department of Ophthalmology, University of Aberdeen, Aberdeen AB25 2ZD, UK. m.zhao@abdn.ac.uk
Song
Bing
B
Pu
Jin
J
Wada
Teiji
T
Reid
Brian
B
Tai
Guangping
G
Wang
Fei
F
Guo
Aihua
A
Walczysko
Petr
P
Gu
Yu
Y
Sasaki
Takehiko
T
Suzuki
Akira
A
Forrester
John V
JV
Bourne
Henry R
HR
Devreotes
Peter N
PN
McCaig
Colin D
CD
Penninger
Josef M
JM
D000818:Animals; D002465:Cell Movement; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004023:Dictyostelium; D004558:Electric Stimulation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing / Q000235:genetics
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051059:PTEN Phosphohydrolase