Induced Pluripotent Stem Cells for Post–Myocardial Infarction Repair

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 suffer 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 HLA 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 of 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 post-MI.

Vascular Wall Progenitor Cells in Health and Disease

“…142 More recently, breakthroughs in pluripotent stem cell research and particularly iPSC technology have heralded exciting new opportunities for patient-specific stem cell-based therapies. 143 Differentiation of iPSCs to hematopoietic and vascular lineages has been achieved using a variety of cell substrates, reprogramming factors and culture protocols. Elcheva et al 144 applied comprehensive gain-of-function screening to identify two optimal combinations of transcription factors capable of inducing discrete types of hematopoietic progenitors from human pluripotent stem cells through a hemogenic endothelium stage: pan-myeloid (ETV2 and GATA-2) and erythromegakaryocytic (GATA-2 and TAL1).…”

Direct Cardiac Reprogramming

“…[8][9][10] However, several issues remain to be resolved before using iPSC-derived cardiomyocytes in the clinic, such as the heterogeneous and relatively immature phenotype of cardiomyocytes generated from stem cells, the possibility of teratoma formation by iPSC contamination, and the poor survival of transplanted cells in the injured heart. 11,12 The discovery of iPSCs in 2006 by Takahashi and Yamanaka [13][14][15] inspired a new approach that generates specific cell types without needing to transition through a stem cell state by introducing combinations of lineage-specific factors, called direct reprogramming.…”

In Vivo Dynamic Metabolic Changes After Transplantation of Induced Pluripotent Stem Cells for Ischemic Injury

“…ESCs could be identified at 2 wk after transplantation on initial studies of fused 18 F-FDG and 9-(4-18 F-fluoro-3-(hydroxymethyl)butyl)guanine imaging (1), and the latter combined with MR imaging presented excellent detection of double labeling of ESCs with the HSV1-sr39tk reporter gene and superparamagnetic iron oxide particles for up to 4 wk in myocardial infarction rats (2). Recently, several studies have reported that iPSC-CMs provide functional benefit after myocardial infarction, although there has been no consensus about the protective mechanism induced by these differentiated cardiomyocytes (11). By using cardiac MRI and comparing with a nontreated control, Wu et al (12) found that iPSC-CMs promoted cardiac protection and attenuated cardiac remodeling after myocardial infarction, despite limited engraftment detected with bioluminescence imaging.…”