Locally delivered growth factor enhances the angiogenic efficacy of adipose-derived stromal cells transplanted to ischemic limbs.
Ischemia is a potentially fatal medical event that is associated with as many as 30% of all deaths. Stem cell therapy offers significant therapeutic promise, but poor survival following transplantation to ischemic tissue limits its efficacy. Here we demonstrate that nanosphere-mediated growth factor delivery can enhance the survival of transplanted human adipose-derived stromal cells (hADSCs) and secretion of human angiogenic growth factors per cell, and substantially improve therapeutic efficacy of hADSCs. In vitro, in hypoxic (1% oxygen) and serum-deprived conditions that simulate in vivo ischemia, fibroblast growth factor-2 (FGF2) significantly reduced hADSC apoptosis and enhanced angiogenic growth factor secretion. In vivo, hADSCs delivered intramuscularly into ischemic hind limbs in combination with FGF2 resulted in significant improvements in limb survival and blood perfusion, as well as survival of the transplanted hADSCs and secretion of human angiogenic growth factors (i.e., vascular endothelial growth factor, hepatocyte growth factor, and FGF2). Interestingly, the majority of transplanted hADSCs were localized adjacent to the microvessels rather than being incorporated into them, suggesting that their major contribution to angiogenesis might be to increase paracrine secretion of angiogenic growth factors. This study demonstrates the potential of hADSCs in combination with growth factors for use in the treatment of ischemia.
Bhang
Suk Ho
SH
Department of Bioengineering, College of Medicine, Hanyang University, Seoul, Korea. bskim@hanyang.ac.kr
Cho
Seung-Woo
SW
Lim
Jae Min
JM
Kang
Jin Muk
JM
Lee
Tae-Jin
TJ
Yang
Hee Seok
HS
Song
Young Soo
YS
Park
Moon Hyang
MH
Kim
Hyo-Soo
HS
Yoo
Kyung-Jong
KJ
Jang
Yangsoo
Y
Langer
Robert
R
Anderson
Daniel G
DG
Kim
Byung-Soo
BS
D000273:Adipose Tissue / Q000166:cytology*; D050154:Adiposity / Q000235:genetics; D043925:Angiogenesis Inducing Agents; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D005455:Fluorescent Antibody Technique; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000601:surgery / Q000628:therapy*; D023821:Limb Salvage; D051379:Mice; D008819:Mice, Nude; D017154:Stromal Cells / Q000637:transplantation*
D043925:Angiogenesis Inducing Agents; D042501:Angiogenic Proteins; D016222:Fibroblast Growth Factor 2