Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model

• Published in: Cell stress & chaperones Vol. 20; no. 4; pp. 643 - 652
• Main Authors: Chen, Young-Bin, Lan, Ying-Wei, Hung, Tsai-Hsien, Chen, Lih-Geeng, Choo, Kong-Bung, Cheng, Winston TK, Lee, Hsuan-Shu, Chong, Kowit-Yu
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 01.07.2015; Springer Netherlands
• Subjects: Angiogenesis; Animals; Aorta - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood vessels; Bone Marrow Cells - cytology; Cancer Research; Cell Biology; Cell Culture Techniques; Cell Differentiation - drug effects; Cell lines; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Coculture Techniques; Cultured cells; Disease Models, Animal; Endothelial cells; Gene therapy; HSP70 Heat-Shock Proteins - genetics; Human Umbilical Vein Endothelial Cells; Humans; Immunology; In Vitro Techniques; Ischemia - metabolism; Ischemia - pathology; Ischemia - therapy; Isomerism; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic - drug effects; Neurosciences; Original Paper; Resveratrol; Scaffolds; Shock heating; Stem cells; Stilbenes - pharmacology; Vascular Endothelial Growth Factor A - metabolism; Angiogenesis; Mouse model; Stem cell-based gene therapy; Hsp70 promoter; Resveratrol; VEGFA
• ISSN: 1355-8145; 1466-1268
• DOI: 10.1007/s12192-015-0588-x

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.