Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells.
BACKGROUND
The delivery of autologous cells to increase angiogenesis is emerging as a treatment option for patients with cardiovascular disease but may be limited by the accessibility of sufficient cell numbers. The beneficial effects of delivered cells appear to be related to their pluripotency and ability to secrete growth factors. We examined nonadipocyte stromal cells from human subcutaneous fat as a novel source of therapeutic cells.


RESULTS
Adipose stromal cells (ASCs) were isolated from human subcutaneous adipose tissue and characterized by flow cytometry. ASCs secreted 1203+/-254 pg of vascular endothelial growth factor (VEGF) per 10(6) cells, 12 280+/-2944 pg of hepatocyte growth factor per 10(6) cells, and 1247+/-346 pg of transforming growth factor-beta per 10(6) cells. When ASCs were cultured in hypoxic conditions, VEGF secretion increased 5-fold to 5980+/-1066 pg/10(6) cells (P=0.0016). The secretion of VEGF could also be augmented 200-fold by transfection of ASCs with a plasmid encoding VEGF (P<0.05). Conditioned media obtained from hypoxic ASCs significantly increased endothelial cell growth (P<0.001) and reduced endothelial cell apoptosis (P<0.05). Nude mice with ischemic hindlimbs demonstrated marked perfusion improvement when treated with human ASCs (P<0.05).


CONCLUSIONS
Our experiments delineate the angiogenic and antiapoptotic potential of easily accessible subcutaneous adipose stromal cells by demonstrating the secretion of multiple potentially synergistic proangiogenic growth factors. These findings suggest that autologous delivery of either native or transduced subcutaneous ASCs, which are regulated by hypoxia, may be a novel therapeutic option to enhance angiogenesis or achieve cardiovascular protection.
Rehman
Jalees
J
Krannert Institute of Cardiology, Indiana Center for Vascular Biology & Medicine, Indianapolis, Ind 46202, USA.
Traktuev
Dmitry
D
Li
Jingling
J
Merfeld-Clauss
Stephanie
S
Temm-Grove
Constance J
CJ
Bovenkerk
Jason E
JE
Pell
Carrie L
CL
Johnstone
Brian H
BH
Considine
Robert V
RV
March
Keith L
KL
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D017930:Genes, Reporter; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D039904:Pluripotent Stem Cells / Q000637:transplantation*; D033581:Stem Cell Transplantation; D017154:Stromal Cells / Q000378:metabolism / Q000637:transplantation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017077:Culture Media, Conditioned; D006133:Growth Substances; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor