Angiopoietin-1 Enhanced Myocytemitosis, Engraftment, And The Reparability Of Hipsc-Cms For Treatment Of Myocardial Infarction

Aims To examine whether transient over-expression of angiopoietin-1 (Ang-1) increases the potency of hiPSC-CMs for treatment of heart failure.Methods and results Atrial hiPSC-CMs (hiPSC-aCMs) were differentiated from hiPSCs and purified by lactic acid and were transfected with Ang-1 (Ang-1-hiPSC-aCMs) plasmid using lipoSTEM. Ang-1 gene transfection efficiency was characterized in vitro. Gene transfected CMs (1x10(6)) were seeded into a fibrin/thrombin patch and implanted on the ratinfarcted left ventricular (LV) anterior wall after myocardial infarction (MI). Echo function was determined at 1- and 6 weeks post-MI. Immunohistochemistry study was performed at 6 weeks post-MI. Ang-1 (20 and 40 ng/mL) protected hiPSC-aCMs from hypoxia through up-regulating pERK1/2 and inhibiting Bax protein expressions. Ang1-hiPSC-aCMs transiently secreted Ang-1 protein up to 14 days, with peak level on day-2 post-transfection (24.39 +/- 13.02 ng/mL) in vitro. Animal study showed that transplantation of Ang-1-hiPSC-aCM seeded patch more effectively limited rat heart apoptosis at 1 day post-MI as compared with LipoSTEM-Ang-1 or hiPSC-aCMs transplantation. Ang-1-hiPSC-aCMs transplantation induced host (rat) and donor (human) CM mitosis and arteriole formation, improved cell engraftment rate, more effectively limited LV dilation (EDV = 460.7 +/- 96.1 mu L and ESV = 219.8 +/- 72.9 mu L) and improved LV global pump function (EF = 53.1 +/- 9%) as compared with the MI (EDV = 570.9 +/- 91.8 mu L, P = 0.033; ESV = 331.6 +/- 71.2 mu L, P = 0.011; EF = 42.3 +/- 4.1%, P = 0.02) or the LipoSTEM-Ang-1 injected (EDV = 491.4 +/- 100.4 mu L, P = 0.854; ESV = 280.9 +/- 71.5 mu L, P = 0.287; EF = 43.2 +/- 4.6, P = 0.039) or hiPSC-CM transplanted (EDV = 547.9 +/- 55.5 mu L, P = 0.095; ESV = 300.2 +/- 88.4 mu L, P = 0.075; EF = 46 +/- 10.9%, P = 0.166) animal groups at 6 weeks post-MI and treatment.Conclusion Transient over-expression of Ang-1 enhanced hiPSC-aCM mitosis and engraftment and increased the reparability potency of hiPSC-aCMs for treatment of MI.