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 better than unmodified MSC.
MSC from C57Bl/6 mice bone marrow were transfected with SCF cDNA cloned into pcDNA-3, 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 (PV) loops on day 28 (n=10 per group). Hearts were perfusion-fixed in situ and cut into transverse sections for computerized planimetry (n=5 per group).
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). All analysis showed significant improvement of post MI ventricular size and function in cell groups compared to M group. PV loop analysis showed a 1.9-fold increase (P<0.001) in the slope of preload-recruitable stroke work in CS group compared with C group. The improvement in end-systolic elastance was similar to the improvement in preload-recruitable stroke work. In addition, the left ventricular volume was 0.6-fold smaller (P<.01) in the CS group compared with the C group. However 4 out of 20 survivors in CS group developed fibrosarcomas infiltrating into the cell transplanted area within 3 months of cell implantation.
Use of genetically modified MSC over-expressing SCF better prevented ventricular dilation and restored cardiac function following MI. Unfortunately, this approach was associated with tumorogenesis and our data strongly suggests that malignant transformation was caused by the specific combination of techniques that we used to generate our cell line.Le texte complet de cet article est disponible en PDF.