Abstract 861: Post Myocardial Infarction Implantation of Mesenchymal Stem Cells Engineered to Over-express Stem Cell Factor Improves Cardiac Function but Results in Tumorogenesis
Background: Myocardial infarction (MI) in mice with mutations in the stem cell factor (SCF) receptor causes rapid heart failure. Implantation of mesenchymal stem cells (MSC) slows progression to heart failure after MI. We hypothesized that MSC engineered to over-express SCF would restore cardiac function toward non-infarcted state better than MSC alone.
Methods: Full length SCF cDNA was cloned into pcDNA-3 backbone, transfected into MSC, and a stable transfectant was selected in G418 medium. C57Bl/6 mice (N) underwent coronary ligation and received medium (M), or 3×105 MSC (C) or MSC transfected with SCF (CS) into the anterior left ventricle. Cardiac function was assessed by pressure-volume loops after fluid-loading on day 28 (n=10 per group). Hearts were perfusion-fixed in situ and cut into 1 mm transverse sections for computerized planimetry (n=5 per group).
Results: When measured in vivo, myocardial SCF increased 2.9-fold in M, 5.5-fold in C, and 17.3-fold in SC groups compared to the N group (P<0.05). End-diastolic pressures were not significantly different between groups (N, 20±1; M, 23±3; C, 20±1; CS, 19±2 mmHg). End-systolic pressures were significantly higher in the cell-treated groups (N, 111±2; M, 89±2; C, 98±3; CS, 99±3 mmHg; P<0.05 M vs S and CS). Preload recruitable stroke work was highest in the N > CS > C > M (N, 814±26; M, 235±17; C, 302±10; CS 574±14 uL.mmHg/uL; P<0.001 for all comparisons). End systolic elastance followed a similar pattern and was highest in N > CS > C > M (N, 86±3; M, 23±2; C, 41±2; CS, 67±2 mmHg/uL; P<0.001 for all comparisons). Heart to body weight ratios and ventricular volumes were best-preserved in CS group (ratio: N, 4±0.01; M, 6±0.4; C, 6±0.3; CS, 5±0.1; P<0.05 C vs CS) (volume: N, 21±1; M, 62±8; C, 38±4; CS, 23±2 uL; P<0.05, M vs C, C vs CS). However, four out of 20 survivors in CS group developed fibrosarcomas infiltrating into the cell transplanted area within 3 months of cell implantation.
Conclusions: Over-expression of SCF by implanted MSC prevents ventricular dilation and restores cardiac function following MI perhaps by increasing the recruitment, homing and engraftment of marrow stem cells expressing the SCF receptor, c-kit. Unfortunately, this approach was associated with tumorogenesis.