Engraftment Is Optimal When Myoblasts Are Transplanted Early: The Role of Hepatocyte Growth Factor

Abstract

In a recent clinical trial, skeletal myoblast (SKMB) transplantation performed late after myocardial infarction (MI) did not improve left ventricular function. We hypothesized that (1) delaying SKMB transplantation until a chronic infarct scar has developed reduces engraftment, and (2) hepatocyte growth factor (HGF), a main regulator of SKMBs, is present in acute but not chronic MI, potentially influencing engraftment. Rats underwent coronary artery ligation followed by SKMB transplantation immediately (n = 12) or delayed by 5 weeks (n = 11). The volume of engrafted SKMBs was quantified 6 weeks later. Hepatocyte growth factor was evaluated by computerized analysis of immunohistochemical labeling of rat heart sections 48 hours, 1 week, 2 weeks, and 5 weeks after coronary artery ligation. The impact of HGF on SKMB proliferation and its ability to protect against oxidative stress and hypoxia was evaluated in vitro. Skeletal myoblast transplantation immediately after MI resulted in an engraftment volume of 29.1 +/- 2.9 mm(3). However, delaying SKMB transplantation 5 weeks caused a 95% drop in engraftment (1.4 +/- 0.3 mm(3); p < 0.001). Hepatocyte growth factor labeling in MIs 48 hours after coronary artery ligation was similar to control myocardium (18.0 +/- 2.0 versus 16.8 +/- 1.3 units). However, HGF declined progressively at 1, 2, and 5 weeks after MI (9.1 +/- 1.4, 4.2 +/- 0.4, and 3.1 +/- 0.6 units, respectively; p < 0.05 versus 48 hours). Hepatocyte growth factor caused a dose-dependent increase in SKMB proliferation in vitro and protected against oxidative stress and hypoxia. These results demonstrate that engraftment of SKMBs is impaired when transplantation is delayed until a chronic infarct has developed. Hepatocyte growth factor in MI declines with time and may enhance engraftment of SKMBs transplanted early after MI. Delivery of exogenous HGF to enhance SKMB engraftment in chronic infarcts warrants further investigation.