Pluripotent Stem Cell Derived Cardiomyocytes for Cardiac Repair

Abstract

Opinion Statement The adult mammalian heart has limited capacity for generation, so a major injury such as a myocardial infarction results in the permanent loss of up to one billion cardiomyocytes. The field of cardiac cell therapy aims to replace these lost contractile units with de novo cardiomyocytes to restore lost systolic function and prevent progression to heart failure. Arguably the ideal cell for this application is the human cardiomyocyte itself, which can electromechanically couple with host myocardium and contribute active systolic force. Pluripotent stem cells from both human embryonic or induced pluripotent lineages are attractive sources for cardiomyocytes, and preclinical investigation of these cells is in progress. Recent work has focused on efficient generation and purification of cardiomyocytes, tissue engineering efforts, and examining the consequences of cell transplantation from mechanical, vascular, and electrical standpoints. Here we discuss historical and contemporary aspects of pluripotent stem cell-based cardiac cell therapy, with an emphasis on recent preclinical studies with translational goals.

Perspectives of induced pluripotent stem cells for cardiovascular system regeneration

“…Proof-of-concept experiments with murine iPSC -cardiomyocytes have shown the ability of these cells to survive and form nascent myocardium. 48 Nelson et al showed that intra-myocardial delivery of iPSCs into the infracted hearts of mice following ligation of the left anterior descending artery yielded progeny that properly engrafted without disrupting cytoarchitecture. 49 Mauritz et al showed that injection of iPSCsderived Flk1-positive progenitor cells into the ischemic myocardium of left anterior descending artery-ligated mice improved cardiac function following myocardial infarction.…”

“…52 The preceding experience in rodent infarct models set the stage for transplantation studies with human iPSC-cardiomyocytes in more relevant large animal preclinical models. 48 Kawamura's group incorporated human iPSCscardiomyocytes into bioengineered sheets that were applied to the epicardial surface of infracted pig hearts. At eight weeks post-transplantation, the recipient hearts had very few surviving graft cells, but they showed better preserved ejection and left ventricular dimensions than untreated controls.…”

The potential and challenges of using stem cells for cardiovascular repair and regeneration

“…In contrast, the use of human inducible pluripotent stem cells (hiPSCs) overcomes the limitations and ethical concerns of hESCs ( Table 1 ). 27 The hiPSCs are derived by reprogramming somatic cells to a pluripotent state. 28 , 29 Several research teams have compared hESCs and hiPSCs and their differentiated progeny.…”

Making it stick: chasing the optimal stem cells for cardiac regeneration

“…Cell culture protocols involving addition of growth factors (BMP4 and activin A), DNA modifiers such as 5-azacytidine and trichostatin A and thyroid hormones help enrich for ES/iPSC-derived cardiomyocytes (70–90%), with accumulation of differentiated cell properties reminiscent of young cardiomyocytes including mono-nucleation with the potential to divide [15-19]. Cardiomyocyte purity and efficiency of ESC differentiation is of critical importance as undifferentiated ESCs may form teratomas and prevent ESC-cardiomyocyte maturation in vivo [17,20]. Unfortunately, reports as to the safety and efficacy of purified ESC-derived myocyte delivery show a reduced capacity to electrically couple with the existing myocardium in both pig and non-human primates despite suppression of arrhythmias in small animal models [17,21].…”