Strategies Using Cell Therapy to Induce Cardiomyocyte Regeneration in Adults with Heart Disease

Abstract

Congestive heart failure remains a major public health problem and is frequently the end result of cardiomyocyte apoptosis and fibrous replacement after myocardial infarction (MI), a process referred to as left ventricular remodeling. Cardiomyocytes undergo terminal differentiation soon after birth and are generally considered to withdraw irreversibly from the cell cycle. In response to ischemic insult, adult cardiomyocytes undergo cellular hypertrophy, nuclear ploidy, and a high degree of apoptosis. A small number of human cardiomyocytes retain the capacity to proliferate and regenerate in response to ischemic injury. However, whether these cells are derived from a resident pool of cardiomyocyte stem cells or from a renewable source of circulating bone marrow—derived stem cells that home to the damaged myocardium is at present not known. Replacement and regeneration of functional cardiac muscle after an ischemic insult to the heart could be achieved either by stimulating proliferation of endogenous mature cardiomyocytes or resident cardiac stem cells, or by implanting exogenous donor-derived or allogeneic cells such as fetal or embryonic cardiomyocyte precursors, bone marrow—derived mesenchymal stem cells, or skeletal myoblasts. The newly formed cardiomyocytes must integrate precisely into the existing myocardial wall in order to augment synchronized contractility and avoid potentially life-threatening alterations in the electrical conduction of the heart. A major impediment to survival of the implanted cells is altered immunogenicity by prolonged ex vivo culture conditions. In addition, concurrent myocardial revascularization is required to ensure viability of the repaired region and prevent further scar tissue formation. Human adult bone marrow contains endothelial precursors, which resemble embryonic angioblasts and can be used to induce infarct bed neovascularization after experimental MI. This results in protection of cardiomyocytes against apoptosis, induction of cardiomyocyte proliferation and regeneration, long-term salvage and survival of viable myocardium, prevention of left ventricular remodeling, and sustained improvement in cardiac function. It is reasonable to anticipate that cell therapy strategies for ischemic heart disease will need to incorporate (1) a renewable source of proliferating, functional cardiomyocytes, and (2) angioblasts to generate a network of capillaries and larger-size blood vessels for supply of oxygen and nutrients to both the chronically ischemic endogenous myocardium and to the newly implanted cardiomyocytes.