Abstract 733: Intracoronary Fibroblast Growth Factor (AdvFGF-5) Increases the Myocardial Localization of CD133+ Hematopoietic Stem Cells (HSCs) in Swine with Hibernating Myocardium
Background: Overexpressing FGF-5 in swine with hibernating myocardium improves function and increases reentry of myocyets into the cell cycle as reflected by increased Ki-67 staining. We tested the hypothesis that this was secondary to increased HSCs homing.
Methods: Swine with hibernating myocardium from a chronic LAD occlusion received i.c. AdvFGF-5 (2 x 1012 vp) in divided doses after pretreatment with i.c. histamine. We assessed regional flow and function 2 weeks (n=8) and 4 weeks (n=5) after AdvFGF-5 vs. untreated hibernating myocardium (n=7) and normal controls (n=5). Histological analysis was performed to quantify myocyte size and myocyte nuclear density. The frequency of myocytes in the growth phase of the cell cycle was evaluated by Ki-67 (clone MIB-1). Myocardial HSCs were quantified using the cell surface marker CD133.
Results: LAD wall thickening increased from 3.0 ± 0.3 mm in untreated to 5.1 ± 0.8 mm 4 weeks after AdvFGF-5 (p<0.05) with no change in resting (0.76 ± 0.08 ml/min/g in untreated to 0.87± 0.1 ml/min/g in FGF-5, p-ns) or vasodilated adenosine flow (0.51 ± 0.15 ml/min/g in untreated to 0.96± 0.23 ml/min/g in FGF-5, p-ns). Histological analysis (Table⇓) demonstrated that AdvFGF-5 increased Ki-67 positive myocytes in parallel with CD133 positive cells (some with GATA-4) with values peaking at 2 weeks and falling 4 weeks after AdvFGF-5. While there was transient myocyte hypertrophy after 2 weeks, myocyte size after 4 weeks was smaller than normal and myocyte nuclear density increased from 926 ± 52 to 1057 ± 50 nuclei/mm2 (p<0.05).
Conclusion: These data indicate that i.c. AdvFGF-5 induces HSCs to home to the heart with a resultant increase in myocytes in the cell cycle (Ki-67 staining), a reduction in myocyte size and an increase in myocyte nuclear density. This raises the possibility that growth factor mediated cardiac repair is secondary to the mobilization of circulating HSCs.