Preconditioning by mitochondrial reactive oxygen species improves the proangiogenic potential of adipose-derived cells-based therapy.
OBJECTIVE
Transplantation of adipose-derived stroma cells (ADSCs) stimulates neovascularization after experimental ischemic injury. ADSC proangiogenic potential is likely mediated by their ability to differentiate into endothelial cells and produce a wide array of angiogenic and antiapoptotic factors. Mitochondrial reactive oxygen species (ROS) have been shown to control ADSC differentiation. We therefore hypothesized that mitochondrial ROS production may change the ADSC proangiogenic properties.


RESULTS
The use of pharmacological strategies (mitochondrial inhibitors, antimycin, and rotenone, with or without antioxidants) allowed us to specifically and precisely modulate mitochondrial ROS generation in ADSCs. We showed that transient stimulation of mitochondrial ROS generation in ADSCs before their injection in ischemic hindlimb strongly improved revascularization and the number of ADSC-derived CD31-positive cells in ischemic area. Mitochondrial ROS generation increased the secretion of the proangiogenic and antiapoptotic factors, VEGF and HGF, but did not affect ADSC ability to differentiate into endothelial cells, in vitro. Moreover, mitochondrial ROS-induced ADSC preconditioning greatly protect ADSCs against oxidative stress-induced cell death.


CONCLUSIONS
Our study demonstrates that in vitro preconditioning by moderate mitochondrial ROS generation strongly increases in vivo ADSC proangiogenic properties and emphasizes the crucial role of mitochondrial ROS in ADSC fate.
Université de Toulouse, UPS, UMR 5241 Métabolisme, Plasticité et Mitochondrie, Toulouse Cedex 4, France.
Audrey
A
Carrière
Téni G
TG
Ebrahimian
Stéphanie
S
Dehez
Nathalie
N
Augé
Carine
C
Joffre
Mireille
M
André
Samuel
S
Arnal
Micheline
M
Duriez
Corinne
C
Barreau
Emmanuelle
E
Arnaud
Yvette
Y
Fernandez
Valérie
V
Planat-Benard
Bernard
B
Lévy
Luc
L
Pénicaud
Jean-Sébastien
JS
Silvestre
Louis
L
Casteilla
D017667:Adipocytes; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000503:physiopathology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
D017382:Reactive Oxygen Species