Myocardial infarction leads to loss of tissue and impairment of cardiac performance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation; these events promote structural and functional repair. This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice. We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein by fluorescence-activated cell sorting on the basis of c-kit expression. Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct. Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells. The developing tissue comprised proliferating myocytes and vascular structures. Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.

The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.

Attempts to repair myocardial infarcts by transplanting cardiomyocytes or skeletal myoblasts have failed to reconstitute healthy myocardium and coronary vessels integrated structurally and functionally with the remaining viable portion of the ventricular wall. The recently discovered growth and transdifferentiation potential of primitive bone marrow cells (BMC) prompted us, in an earlier study, to inject in the border zone of acute infarcts Lin ؊ c-kit POS BMC from syngeneic animals. These BMC differentiated into myocytes and vascular structures, ameliorating the function of the infarcted heart. Two critical determinants seem to be required for the transdifferentiation of primitive BMC: tissue damage and a high level of pluripotent cells. On this basis, we hypothesized here that BMC, mobilized by stem cell factor and granulocyte-colony stimulating factor, would home to the infarcted region, replicate, differentiate, and ultimately promote myocardial repair. We report that, in the presence of an acute myocardial infarct, cytokine-mediated translocation of BMC resulted in a significant degree of tissue regeneration 27 days later. Cytokineinduced cardiac repair decreased mortality by 68%, infarct size by 40%, cavitary dilation by 26%, and diastolic stress by 70%. Ejection fraction progressively increased and hemodynamics significantly improved as a consequence of the formation of 15 ؋ 10 6 new myocytes with arterioles and capillaries connected with the circulation of the unaffected ventricle. In conclusion, mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of ischemic heart disease and, perhaps, other forms of cardiac pathology.

Summary Background C-kit+ lineage− cardiac stem cells (CSCs) improve postinfarction left ventricular (LV) dysfunction in animals; however, their efficacy in humans is unknown. Methods In February 2009, we began SCIPIO (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy), a Phase I, randomized, open-label trial of CSCs in patients with postinfarction LV dysfunction (ejection fraction [EF] ≤ 40%) who underwent coronary bypass surgery. Autologous CSCs were isolated from the right atrial appendage and re-infused intracoronarily 4 ± 1 months after surgery; controls received no treatment. In Stage A, 9 treated and 4 control patients were consecutively enrolled to assess the feasibility and short-term safety of CSCs. Then, in Stage B, patients were randomized to the treated or control arm in a 2:3 ratio using a block randomization scheme and a block size of five. Primary (safety) and secondary (efficacy) endpoints were assessed at serial times after enrollment. Findings Autologous CSCs were successfully isolated and expanded in 80 out of 81 patients. In 16 treated patients, no CSC-related adverse effects have been observed. LVEF (3D echocardiography) increased from 30.3 ± 1.9% before CSC infusion to 38.5 ± 2.8% at 4 months after infusion, (P=0.001, n=14). This was associated with an improvement in regional wall motion score index (echocardiography) (1.91 ± 0.09 vs. 1.73 ± 0.09, P=0.005), NYHA functional class (2.19 ± 0.16 vs. 1.63 ± 0.16, P=0.003), and quality of life (MLHFQ score, 46.44 ± 5.22 vs. 26.69 ± 4.92, P<0.0001). In contrast, in 7 control patients, none of these variables changed appreciably during the corresponding time-interval. Importantly, the salubrious effects of CSCs were even more pronounced at 1 year (e.g., LVEF increased by 12.3 ± 2.1% vs. pre-CSCs, P=0.0007, n=8), suggesting that CSCs continue to improve LV function beyond the first 4 months. In the 7 treated patients in whom cardiac magnetic resonance (cMR) imaging could be performed, infarct size decreased by 7.8 ± 1.7 g (23.8%) at 4 months (P=0.004) and 9.8 ± 3.5 g (30.3%) at 1 year (P=0.04). Interpretation These initial results in humans are very encouraging, and suggest that infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure.