Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges

Abstract

Coronary artery disease with associated myocardial infarction continues to be a major cause of death and morbidity around the world, despite significant advances in therapy. Patients who have large myocardial infarctions are at highest risk for progressive heart failure and death, and cell-based therapies offer new hope for these patients. A recently discovered cell source for cardiac repair has emerged as a result of a breakthrough reprogramming somatic cells to induced pluripotent stem cells (iPSCs). The iPSCs can proliferate indefinitely in culture and can differentiate into cardiac lineages, including cardiomyocytes, smooth muscle cells, endothelial cells, and cardiac progenitors. Thus, large quantities of desired cell products can be generated without being limited by cellular senescence. The iPSCs can be obtained from patients to allow autologous therapy or, alternatively, banks of human leukocyte antigen diverse iPSCs are possible for allogeneic therapy. Preclinical animal studies using a variety of cell preparations generated from iPSCs have shown evidence of cardiac repair. Methodology for the production of clinical grade products from human iPSCs is in place. Ongoing studies for the safety of various iPSC preparations with regard to the risk of tumor formation, immune rejection, induction of arrhythmias, and formation of stable cardiac grafts are needed as the field advances toward the first-in-man trials of iPSCs after myocardial infarction.

Keywords: cell- and tissue-based therapy; induced pluripotent stem cell; myocardial infarction; regenerative medicine; tissue engineering.

Figure 1. Potential mechanisms of benefit of cell therapy to the post-MI heart

Transplanted cells exert beneficial effects on the damaged myocardium by multiple potential mechanisms. Regeneration of new myocardium from delivered cells is the most appealing mechanism; however, most pre-clinical and clinical studies to date have suggested that the beneficial effects of post-MI cell therapy are due to paracrine signaling. Paracrine signaling can reduce apoptosis in surviving cells, promote cell cycle activation for repair, prevent adverse immune remodeling, activate endogenous stem cells and induce neo-vascularization. The optimal cell therapy will likely harness multiple of these potential mechanisms for successful cardiac repair.

Figure 2. Cardiac cell therapy strategies using iPSCs and derivatives

Patient-specific primary cells are isolated and cultured in-vitro from a suitable cell source such as blood or skin. These cells are reprogrammed to iPSCs utilizing non-integrating strategies under cGMP conditions. The resulting iPSCs are rigorously tested for pluripotency, genetic/epigenetic abnormalities and safety (Table 3,4). The iPSC clones that pass test criteria are banked for later use. Alternatively, allogeneic iPSCs can be utilized from a haplotype-matched iPSC bank. The iPSCs are then be differentiated into the desired cardiac lineage cells: cardiac progenitors, cardiomyocytes, smooth muscle cells or endothelial cells. The desired cell lineage or combination of cell lineages are transplanted into damaged heart via intracoronary/intramuscular injection or epicardially by tissue engineered cardiac patches. Ongoing studies will define he optimal cell preparations and associated delivery strategies for repair of the post-MI heart.

Figure 3. Arrhythmia risk from cellular therapies

Cell therapy has the potential to induce as well as prevent arrhythmias in the post-MI heart. Potential mechanisms for antiarrhythmic and proarrhythmic effects are listed.