Back to 85th Annual Meeting
Back to Program Outline

L1. Stem Cell Factor is Required for Cardiac Regeneration
Shafie Fazel, Liwen Chen, Richard D Weisel, Denis Angoulvant, Phillip Cheung, Amir Fazel, Jason Lam, Paul WM Fedak, Terrence M Yau, Ren-ke Li; Toronto, ON, Canada

Objective: Stem cell factor (SCF) was found to be important in cardiac repair after myocardial infarction (MI). We evaluated the influence of SCF on endothelial progenitor cell (EPC) mobilization following ischemia, because SCF receptor-expressing EPCs are suspected to home to MI and aid cardiac regeneration.
Methods: Cardiac function at 42 days (D) was evaluated after coronary ligation in mutant mice with functional deficiency of the SCF receptor c-kit (W/W^v) and compared to wild type (WT). The fluctuations in SCF were evaluated following cardiac ischemia induced by 60 minutes of coronary occlusion produced without a thoracotomy to segregate surgical trauma from effects of ischemia/reperfusion injury (IR): at D-7 the left coronary artery was looped by a suture whose ends were exteriorized; at D0 the ends were placed under tension to occlude the coronary artery using only a small (<5 mm) skin incision with ECG monitoring. In every instance ST elevation confirmed ischemia and ST normalization confirmed reperfusion. On D0, 1, 3, and 7 after IR, organ samples were collected and assayed. EPC and marrow progenitors were quantified by ex-vivo culture techniques. Percentages indicate changes normalized to base-line.
Results: Coronary occlusion produced a similar infarct in both c-kit mutant and WT mice. At D42 morphometry demonstrated greater ventricular dilatation (WT 49+/-8; W/W^v 88+/-8 ul, p<0.05) and echocardiography demonstrated greater decrease in fractional area contraction (WT 34+/-4; W/W^v 13+/-2%, p<0.05) in the mutant mouse. Because SCF may be required for cardiac regeneration, the influence of cardiac ischemia on SCF fluctuations was evaluated. After IR, soluble SCF (sSCF) increased in plasma (max D1: 134±15%, P<0.05) and bone marrow (max D1: 260±98%, P=0.08). Two days later, SCF mRNA was up-regulated and SCF protein was increased in the muscle beyond the temporary coronary occlusion but not the non-injured region of the heart. Immunohistochemistry localized SCF to the venules of the injured region. The fluctuations in plasma SCF levels temporally corresponded to EPC mobilization (max D1: 243±60%, P<0.05). Similarly, the timing for the increased myocardial SCF levels corresponded to the timing of c-kit⁺ cell infiltration (max injured D3: 255±48%, P<0.05) and marrow progenitor cell infiltration (D0: 0±0; max D3: 15.3±0.8 CFU/IR_area, P<0.05) in the injured region of the heart. Increased regional SCF level was associated with c-kit phosphorylation, confirming the physiologic coupling of SCF and its receptor.
Conclusions: SCF activation aids EPC trafficking to ischemic myocardium, and blocking of this pathway contributes to adverse cardiac remodeling after MI. Regional over-expression of SCF in cells transplanted into the infarct region may enhance cardiac regeneration and restore function to the infarct.

Back to 85th Annual Meeting
Back to Program Outline