Unlocking the Pragmatic Potential of Regenerative Therapies in Heart Failure with Next-Generation Treatments

Abstract

Patients with chronic heart failure (HF) have a poor prognosis due to irreversible impairment of left ventricular function, with 5-year survival rates <60%. Despite advances in conventional medicines for HF, prognosis remains poor, and there is a need to improve treatment further. Cell-based therapies to restore the myocardium offer a pragmatic approach that provides hope for the treatment of HF. Although first-generation cell-based therapies using multipotent cells (bone marrow-derived mononuclear cells, mesenchymal stem cells, adipose-derived regenerative cells, and c-kit-positive cardiac cells) demonstrated safety in preclinical models of HF, poor engraftment rates, and a limited ability to form mature cardiomyocytes (CMs) and to couple electrically with existing CMs, meant that improvements in cardiac function in double-blind clinical trials were limited and largely attributable to paracrine effects. The next generation of stem cell therapies uses CMs derived from human embryonic stem cells or, increasingly, from human-induced pluripotent stem cells (hiPSCs). These cell therapies have shown the ability to engraft more successfully and improve electromechanical function of the heart in preclinical studies, including in non-human primates. Advances in cell culture and delivery techniques promise to further improve the engraftment and integration of hiPSC-derived CMs (hiPSC-CMs), while the use of metabolic selection to eliminate undifferentiated cells will help minimize the risk of teratomas. Clinical trials of allogeneic hiPSC-CMs in HF are now ongoing, providing hope for vast numbers of patients with few other options available.

Keywords: CM; cardiomyocyte; heart failure; hiPSC; human-induced pluripotent stem cell; iPSC; induced pluripotent stem cell.

Figure 1

Mechanism of action of next-generation cell therapies versus first-generation cell therapies. In contrast to first-generation therapies, which are largely limited to paracrine effects, next-generation therapies aim to promote remuscularization of the heart. BM-MNC, bone marrow-derived mononuclear cell; CM, cardiomyocyte; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; hiPSC-CM, human-induced pluripotent stem cell-derived cardiomyocyte; LV, left ventricle; LVEF, left ventricular ejection fraction; miRNA, micro ribonucleic acid; MSC, mesenchymal stem cell; SDF-1, stromal cell-derived factor-1; VEGF, vascular endothelial growth factor.

Figure 2

Overview of implantation methods and devices for engrafting hiPSC-CMs. hiPSC, human-induced pluripotent stem cell-derived cardiomyocyte; LAD, left anterior descending; LCX, left circumflex coronary artery; LV, left ventricle; RCA, right coronary artery.

Figure 3

Overview of the scalable manufacturing of clinical-grade hiPSC-CMs. CM, cardiomyocyte; hiPSC, human-induced pluripotent stem cell; hiPSC-CM, human-induced pluripotent stem cell-derived cardiomyocyte; w/o, without.