title: Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model.
abstract: Several studies of stem cell-based gene therapy have indicated that long-lasting regeneration following vessel ischemia may be stimulated through VEGFA gene therapy and/or MSC transplantation for reduction of ischemic injury in limb ischemia and heart failure. The therapeutic potential of MSC transplantation can be further improved by genetically modifying MSCs with genes which enhance angiogenesis following ischemic injury. In the present study, we aimed to develop an approach in MSC-based therapy for repair and mitigation of ischemic injury and regeneration of damaged tissues in ischemic disease. HSP70 promoter-driven VEGFA expression was induced by resveratrol (RSV) in MSCs, and in combination with known RSV biological functions, the protective effects of our approach were investigated by using ex vivo aortic ring coculture system and a 3D scaffolds in vivo model. Results of this investigation demonstrated that HSP promoter-driven VEGFA expression in MSC increased approximately 2-fold over the background VEGFA levels upon HSP70 promoter induction by RSV. Exposure of HUVEC cells to medium containing MSC in which VEGFA had been induced by cis-RSV enhanced tube formation in the treated HUVEC cells. RSV-treated MSC cells differentiated into endothelial-like phenotypes, exhibiting markedly elevated expression of endothelial cell markers. These MSCs also induced aortic ring sprouting, characteristic of neovascular formation from pre-existing vessels, and additionally promoted neovascularization at the MSC transplantation site in a mouse model. These observations support a hypothesis that VEGFA expression induced by cis-RSV acting on the HSP70 promoter in transplanted MSC augments the angiogenic effects of stem cell gene therapy. The use of an inducible system also vastly reduces possible clinical risks associated with constitutive VEGFA expression.
authors: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China.
authors: Young-Bin
authors: YB
authors: Chen
authors: Ying-Wei
authors: YW
authors: Lan
authors: Tsai-Hsien
authors: TH
authors: Hung
authors: Lih-Geeng
authors: LG
authors: Chen
authors: Kong-Bung
authors: KB
authors: Choo
authors: Winston T K
authors: WT
authors: Cheng
authors: Hsuan-Shu
authors: HS
authors: Lee
authors: Kowit-Yu
authors: KY
authors: Chong
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007536:Isomerism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D000077185:Resveratrol