Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles.
Stem cells hold great potential as cell-based therapies to promote vascularization and tissue regeneration. However, the use of stem cells alone to promote angiogenesis remains limited because of insufficient expression of angiogenic factors and low cell viability after transplantation. Here, we have developed vascular endothelial growth factor (VEGF) high-expressing, transiently modified stem cells for the purposes of promoting angiogenesis. Nonviral, biodegradable polymeric nanoparticles were developed to deliver hVEGF gene to human mesenchymal stem cells (hMSCs) and human embryonic stem cell-derived cells (hESdCs). Treated stem cells demonstrated markedly enhanced hVEGF production, cell viability, and engraftment into target tissues. S.c. implantation of scaffolds seeded with VEGF-expressing stem cells (hMSCs and hESdCs) led to 2- to 4-fold-higher vessel densities 2 weeks after implantation, compared with control cells or cells transfected with VEGF by using Lipofectamine 2000, a leading commercial reagent. Four weeks after intramuscular injection into mouse ischemic hindlimbs, genetically modified hMSCs substantially enhanced angiogenesis and limb salvage while reducing muscle degeneration and tissue fibrosis. These results indicate that stem cells engineered with biodegradable polymer nanoparticles may be therapeutic tools for vascularizing tissue constructs and treating ischemic disease.
Yang
Fan
F
Department of Chemical Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cho
Seung-Woo
SW
Son
Sun Mi
SM
Bogatyrev
Said R
SR
Singh
Deepika
D
Green
Jordan J
JJ
Mei
Ying
Y
Park
Sohyun
S
Bhang
Suk Ho
SH
Kim
Byung-Soo
BS
Langer
Robert
R
Anderson
Daniel G
DG
D000818:Animals; D001672:Biocompatible Materials; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D005121:Extremities / Q000098:blood supply / Q000473:pathology; D005355:Fibrosis; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000601:surgery; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology; D053758:Nanoparticles; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011108:Polymers / Q000737:chemistry*; D012038:Regeneration / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D001672:Biocompatible Materials; D011108:Polymers; D042461:Vascular Endothelial Growth Factor A; C507253:poly(beta-amino ester)