Myoblast transplantation is limited by the massive and early death of the majority of transplanted cells. This massive death may be partly due to the reduction of the arterial blood supply within the injection zone generally due to damage, constriction or blocking of blood vessels contributing to hypoxia. Vascular endothelial growth factor (VEGF) is secreted by endothelial cells to promote neo-vascularization. VEGF acts on endothelial progenitor cells by encouraging their proliferation, migration and survival. VEGF is also produced in cells that have a limited oxygen supply. These oxygen deficient cells produce the hypoxia inducible factor (HIF) that stimulates the release of VEGF. In light of recent studies demonstrating that VEGF transient over-expression prolongs islet survival after transplantation, this study led by Dr. Jacques Tremblay aimed to evaluate the implication of hypoxia in the early death of transplanted myoblasts. They also verified whether VEGF could improve the survival and/or proliferation. Pimonidazole hydrochloride labeling showed that the majority of transplanted myoblasts were hypoxic, indicating that the injection procedure restricts oxygen supply to the cells. To investigate whether VEGF could enhance cell survival in vivo, female SCID mouse TA muscles were electroporated with the VEGF plasmid and radioactive human male myoblasts were transplanted several days later. The results demonstrated that VEGF reduced myoblast hypoxia and promoted angiogenesis. VEGF enhanced transplanted human myoblast survival and their engraftment but did not improve their proliferation. Elevated levels of human VEGF enhanced by 1.4-fold 4 days following their transplantation. Furthermore, graft success was 1.3-fold higher in mice electroporated with the plasmid coding for VEGF than in control mice electroporated with the empty vector. The data from this study imply that hypoxia is partially involved in the death of transplanted myoblasts and that VEGF treatment is a potential method to improve their survival.
This work was partly funded by the AFM.


Références : Gene Ther. 2007 Dec 13; [Epub ahead of print]