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Cell Stress and Chaperones

, Volume 20, Issue 4, pp 643–652 | Cite as

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

  • Young-Bin Chen
  • Ying-Wei Lan
  • Tsai-Hsien Hung
  • Lih-Geeng Chen
  • Kong-Bung Choo
  • Winston TK Cheng
  • Hsuan-Shu Lee
  • Kowit-Yu Chong
Original Paper

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.

Keywords

Stem cell-based gene therapy Resveratrol Hsp70 promoter VEGFA Angiogenesis Mouse model 

Notes

Acknowledgments

This work was supported in part by the Ministry of Science and Technology (Taiwan), NSC 99-2632-B-182-001-MY3 and MOST 103-2320-B-182-021, Chang Gung Memorial Hospital Grant (CMRPD 34012, CMRPD 180133, CMRPD1B0472, CMRPD1B0473), and the Ministry of Education, Taiwan (EMRPD1C0121).

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Copyright information

© Cell Stress Society International 2015

Authors and Affiliations

  • Young-Bin Chen
    • 1
  • Ying-Wei Lan
    • 2
  • Tsai-Hsien Hung
    • 2
  • Lih-Geeng Chen
    • 6
  • Kong-Bung Choo
    • 7
  • Winston TK Cheng
    • 8
  • Hsuan-Shu Lee
    • 1
    • 9
  • Kowit-Yu Chong
    • 2
    • 3
    • 4
    • 5
  1. 1.Institute of BiotechnologyNational Taiwan UniversityTaipeiRepublic of China
  2. 2.Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of MedicineChang Gung UniversityTao-YuanRepublic of China
  3. 3.Department of Medical Biotechnology and Laboratory Sciences, College of MedicineChang Gung UniversityTao-YuanRepublic of China
  4. 4.Molecular Medicine Research Center, College of MedicineChang Gung UniversityTao-YuanRepublic of China
  5. 5.Department of Family MedicineChang Gung Memorial Hospital-LinkouTaoyuanRepublic of China
  6. 6.Department of Microbiology, Immunology and Biopharmaceuticals, College of Life SciencesNational Chiayi UniversityChiayiRepublic of China
  7. 7.Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell ResearchUniversiti Tunku Abdul RahmanSelangorMalaysia
  8. 8.Department of Animal Science and BiotechnologyTunghai UniversityTaichungRepublic of China
  9. 9.Department of Internal MedicineNational Taiwan University Hospital and National Taiwan University College of MedicineTaipeiRepublic of China

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