MAST CELL TRANSPLANTATION IMPROVES INFARCT HEALING BUT DOES NOT RESTORE YOUTHFUL CARDIAC REGENERATION TO OLD MICE

Abstract

Following coronary occlusion, myocardial infarct (MI) healing requires a balance between inflammatory cell infiltration and regenerative cell recruitment. Mast cells modulate cell migration after an MI and may be essential for infarct healing since mast cell-depleted mice have rapidly expanding infarcts and die. In addition, old mice have stem cell dysfunction and a diminished regenerative response to MI. This study was designed to evaluate the effects of mast cell transplantation after an MI on the inflammatory response and recovery of ventricular function. Mast cell injections may restore cardiac infarct healing in aged mice. Fresh bone marrow-derived mast cells (BMMCs) from young donors (6-8 weeks old) were implanted immediately after permanent left coronary artery ligation into young (8-12 weeks old, BMMC-Y) and aged (18-20 month old, BMMC-O) recipient mice, respectively. The control groups included young (8-12 weeks old, Y control) and aged (18-20 month old, O control) mice which received medium injection after coronary ligation. Cardiac function was evaluated by echocardiography over the entire 4 weeks of the study after the MI. Cytokine production was measured by enzyme-linked immunosorbent assay (ELISA) at 3 days after an MI. Inflammatory cell infiltration was evaluated by flow cytometry 3 days after MI. Scar formation was documented at the end of the study (28 days). BMMC implantation increased macrophage infiltration similarly in both the young and aged groups, but increased neutrophil infiltration more in the old (BMMC-O) group compared with all the other groups (p<0.05). This heightened inflammatory response was associated with higher levels of transforming growth factor-β (TGF-β) in the BMMC-O group. In contrast, basic fibroblast growth factor (bFGF) was increased with mast cell transplantation compared to the media injected control groups, but was higher in the BMMC-Y than the BMMC-O group (p<0.05). BMMC implantation attenuated the decline of fractional shortening after MI and the scar was significantly thicker in both BMMC groups compared to the media injected controls (p<0.05). However, ventricular function was consistently better in the BMMC-Y than the BMMC-O group after MI (p<0.05). After MI, BMMC transplantation induced a more robust inflammatory and regenerative cell response and cytokine release than the media injected controls. However, BMMC implantation did not completely restore the regenerative defects in aged mice. Although important for infarct healing, mast cell implantation did not restore youthful regeneration to old mice after an MI.