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Title: Cell-based gene therapy for mending infarcted hearts
Author: Poudel, Bhawana
ISNI:       0000 0004 2699 5464
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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The goal of this study was to analyse the efficiency of a combinatorial cell/growth factor therapy to improve function of infarcted murine hearts. The Insulin-like Growth Factor-1 (IGF-1) isoform, IGF-1Ea, has been shown to reduce scar formation and decrease cell death after MI. The present study utilized P19Cl6-derived, IGF-1Ea over-expressing cardiomyocytes to achieve its goal. The P19Cl6 cells were stably transduced with IGF-1Ea using a lentiviral vector and investigated first in vitro for their feasibility for in vivo cell therapy. The engineered pluripotent cells over-expressing IGF-1Ea survived better to hypoxia-induced injury than the control cells. The cells maintained their pluripotency and efficient differentiation capacity towards ventricular cardiomyocyte lineage, generating large quantities of cardiomyocytes optimal for the transplantation study. The generated cardiomyocytes were functionally active and exhibited a mature phenotype. Transplantation of the cardiomyocytes into allogeneic wild type murine infarcted hearts conferred a tendency for maintenance of function at short-term time point. At long-term however, this effect was lost, returning to the level of the control infarcted hearts. Cell tracing assessment revealed engraftment of both IGF-1Ea- and empty-cells, although the cells failed to couple with the recipient tissue. Scar size and capillary density analyses revealed no significant difference between the cells transplanted compared to the saline treated hearts, corroborating with the long-term functional data. Interestingly, the IGF- 1Ea-cell transplanted hearts expressed significantly higher amount of VEGFa compared to the controls, albeit no change in capillary density. Further investigation revealed that the enhanced VEGFa expression in IGF-1Ea-cells transplanted hearts was associated with reduced hypertrophy, marked by reduced cell cross-sectional area at the border-zone, aSK and bMHC expression compared to the control hearts. Nonetheless, modulation of hypertrophic response and transplantation of IGF-1Ea-cells were not able to confer lasting functional preservation, possibly due to lack of sufficient engraftment and coupling of the transplanted cells.
Supervisor: Rosenthal, Nadia ; Santini, Maria Sponsor: EMBO
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral