Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles

Fan Yang, Seung Woo Cho, Sun Mi Son, Said R. Bogatyrev, Deepika Singh, Jordan J. Green, Ying Mei, Sohyun Park, Suk Ho Bhang, Byung Soo Kim, Robert Langer, Daniel G. Anderson

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224 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3317-3322
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number8
DOIs
Publication statusPublished - 2010 Feb 23

All Science Journal Classification (ASJC) codes

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    Yang, F., Cho, S. W., Son, S. M., Bogatyrev, S. R., Singh, D., Green, J. J., Mei, Y., Park, S., Bhang, S. H., Kim, B. S., Langer, R., & Anderson, D. G. (2010). Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles. Proceedings of the National Academy of Sciences of the United States of America, 107(8), 3317-3322. https://doi.org/10.1073/pnas.0905432106