No abstract

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair. myocardial infarction ͉ myocardial regeneration W ith the recent surge of interest in cardiac regenerative therapies for patients with acute myocardial infarction (MI) (1), the identification of clinically applicable strategies is of paramount importance. Several cell types have been used in an effort to reconstitute dead myocardium. Among them, endothelial progenitor cells and bone marrow-derived cells have been the most successful (2-6). However, preliminary long-term studies with bone marrow-derived cells indicate that the new myocytes do not acquire the adult phenotype but resemble neonatal cells, which die with time by apoptosis (P.A., unpublished data). Intense efforts continue to focus on identifying an effective cell population and an effective mode of delivery.The discovery that the adult heart contains a pool of cardiac stem cells (CSCs) that can replenish the cardiomyocyte population and generate coronary vessels (7-12) has dramatically changed the traditional view of the heart as a postmitotic organ. Because of its natural role in regeneration of cardiac cells, the endogenous CSC appears to be the ideal cell for myocardial repair. Recent studies have shown that when c-kit POS CSCs are injected directly into the myocardium adjacent to an infarct produced by a permanent coronary occlusion, they migrate to the infarct and reconstitute part of the dead tissue, reducing infarct size and ameliorating cardiac function in rats (9) and mice (12). In contrast, i.v. injection of CSCs in mice subje...

IL-6 does not modulate myocardial infarct size in naïve myocardium. However, following a PC stimulus, IL-6 is obligatorily required for the activation of the JAK-STAT pathway, the ensuing upregulation of iNOS and COX-2 (co-mediators of late PC), and the development of a cardioprotective phenotype.

Abstract-We systematically investigated the comparative efficacy of three different cytokine regimens, administered after a reperfused myocardial infarction, in regenerating cardiac tissue and improving left ventricular (LV) function. Wild-type (WT) mice underwent a 30-minute coronary occlusion followed by reperfusion and received vehicle, granulocyte colony-stimulating factor (G-CSF)ϩFlt-3 ligand (FL), G-CSFϩstem cell factor (SCF), or G-CSF alone starting 4 hours after reperfusion. In separate experiments, chimeric mice generated by reconstitution of radioablated WT mice with bone marrow from enhanced green fluorescent protein (EGFP) transgenic mice underwent identical protocols. Mice were euthanized 5 weeks later. Echocardiographically, LV function was improved in G-CSFϩFL-and G-CSFϩSCF-treated but not in G-CSF-treated mice, whereas LV end-diastolic dimensions were smaller in all three groups. Morphometrically, cytokine-treated hearts had smaller LV diameter and volume. Numerous EGFP-positive cardiomyocytes, capillaries, and arterioles were noted in the infarcted region in cytokine-treated chimeric mice treated with G-CSFϩFL or G-CSFϩSCF, but the numbers were much smaller in G-CSF-treated mice. G-CSFϩFL therapy mobilized bone marrow-derived cells exhibiting increased expression of surface antigens (CD62L and CD11a) that facilitate homing. We conclude that postinfarct cytokine therapy with G-CSFϩFL or G-CSFϩSCF limits adverse LV remodeling and improves LV performance by promoting cardiac regeneration and probably also by exerting other beneficial actions unrelated to regeneration, and that G-CSF alone is less effective. , no therapies are currently available to restore dead myocardium. Although mobilization of bone marrow cells (BMCs) by cytokines has been suggested to regenerate cardiac tissue after MI and to produce functional improvement, the reports on the effects of cytokine treatment are conflicting. [1][2][3][4][5][6] Furthermore, previous studies of cytokines have used models of permanent coronary ligation 1-3,5 that do not reflect the fact that most patients with acute MI undergo coronary reperfusion. In addition, these studies have administered cytokines as a pretreatment 1,2 or performed splenectomy 1,2,5 or both, 1,2 neither of which would be clinically feasible. Although various cytokines have been tested, the relative efficacy of different treatments or combinations of treatments has not been elucidated. Finally, the mechanism whereby cytokines improve left ventricular (LV) function and structure after MI remains obscure. It has been proposed that cytokines mobilize BMCs with subsequent homing to the infarcted tissue and transdifferentiation into cardiac lineage, 1-3 but this hypothesis remains unproven. Thus, numerous unresolved issues persist regarding the use of cytokines as a strategy to achieve cardiac repair after MI.Accordingly, in the present study, we examined the effect of three cytokines (granulocyte colony-stimulating factor [G-CSF], stem cell factor [SCF], and Flt-3 ligand [FL]) on ca...