Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction

Induced pluripotent stem cell (iPSC)-derived cardiovascular progenitor cells represent a suitable autologous cell source for myocardial regeneration as they have the capability to form myocardial cells and to contribute to revascularization. As a first proof of concept we evaluated the potential of a murine iPSC-derived cardiovascular progenitor population, which expresses the surface marker foetal liver kinase-1 (Flk-1), to restore myocardial tissue and improve cardiac function after acute myocardial infarction (MI) in mice.

iPSC-derived Flk-1^pos vs. Flk-1^neg cells were selected by fluorescence activated cell sorting (FACS) and injected into the ischaemic myocardium of left anterior descending coronary artery (LAD)-ligated mice. Addressing safety aspects we used an octamer binding factor 4 (Oct4)-enhanced green fluorescent protein (eGFP) expressing iPSC clone from the transgenic Oct4-eGFP reporter mouse strain OG2 to enable FACS-based depletion of undifferentiated cells prior to transplantation. Infarcted animals were treated with placebo (phosphate-buffered saline, n = 13), Flk-1^neg cells (n = 14), or Flk-1^pos cells (n = 11; 5 × 10⁵ cells each). Heart function was evaluated by magnetic resonance imaging and conductance catheter analysis 2 weeks postoperatively. Cardiovascular in vitro and in vivo differentiations were investigated by immunofluorescence staining. Treatment with Flk-1^pos and Flk-1^neg cells resulted in a favourable myocardial remodelling and improved left ventricular function. Engraftment and functional benefits were superior after transplantation of Flk-1^pos compared with Flk-1^neg cells. Furthermore, Flk-1^pos grafts contained considerably more vascular structures in relation to Flk-1^neg grafts.

iPSC-derived Flk-1^pos progenitor cells differentiate into cardiovascular lineages in vitro and in vivo and improve cardiac function after acute MI. This proof of concept study paves the way for an autologous iPSC-based therapy of MI.