Cardiac stem cell therapy administered at the time of infarction effectively blunts cardiomyopathic damage a few weeks after treatment but long term efficacy of adoptive stem cell transfer remains largely unknown. A comparative analysis shows that long term (25 week) protection is only provided by Pim-1 modified progenitor cells whereas unmodified progenitor cells fail to provide prolonged benefits after six weeks post intramyocardial injection. After infarction mice were intramyocardially injected with saline, unmodified cardiac progenitor cells (CPC’s), or Pim-1 modified CPC’s. At a 12 week time point mice injected with Pim-1 modified CPC’s have increased EF and FS as compared to mice injected with unmodified cells (n=15 for each group). Invasive hemodynamic measurements (n=5 for each group) confirm that mice injected with Pim-1 modified CPC’s had improved performance by assessment of multiple functional criteria compared to unmodified cells. Longitudinal monitoring by echocardiography reveals that mice injected with Pim-1 modified CPC’s sustain fractional shortening and ejection fraction for up to 24 weeks whereas animals that receive unmodified cells begin to fail within 6 weeks after delivery and were not statistically different than saline injected controls after 12 weeks. In addition Pim-1 CPC injected mice had infarct sizes 52% smaller than control groups (p<.02). Both saline and unmodified CPC’s groups maintained similar infarct sizes (~60% of left ventricular free wall). Confocal microscopy reveals engraftment and persistence of injected Pim-1 CPC’s into the myocardium with differentiation into multiple cardiogenic lineages giving rise to myocytes, vasculature, and endothelium Successful long term functional improvement of the heart requires the engraftment of Pim-1 genetically modified cardiac progenitor cells. Unmodified cells offer an acute ameliorative response but ultimately fail in the ability to effectively repair and maintain the function of the heart. These results support use of genetic engineering to enhance stem cell-mediated myocardial regeneration.
Increased baseline RASGRP1 signals enhance stem cell fitness during native hematopoiesis
