Postinfarct Cytokine Therapy Regenerates Cardiac Tissue and Improves Left Ventricular Function

Abstract

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...

Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction

“…BM-derived cells (BMCs) have been shown to participate in tissue repair following injury to several organs, including the brain, liver, lung, kidney [1][2][3][4][5] as well as the heart [6][7][8][9][10][11]. Cardiomyocytes derived from BMCs have been noted in the heart after myocardial infarction (MI) [6,7,10]. The egress of primitive cells from the BM into the blood is an essential first step for effective tissue repair by BMCs [12,13].…”

Cytokine Treatment Improves Parenchymal and Vascular Damage of Salivary Glands after Irradiation

“…The regenerated/newly formed blood vessels, especially after F/S/G treatment, were partly bone marrow-derived, as indicated by the capillary coexpression of CD31 and eGFP. This is the first time such an observation has been reported in irradiated vessels, although it has been shown to occur after ischemia in arterioles and capillaries of the limb (48,49) and the infarcted heart (27,31). The more pronounced improvement of the vasculature after F/S/G treatment may be due to an enhanced mobilization of endothelial progenitor cells, which are not only capable of differentiating into endothelial cells (50) but can also release growth factors that act in a paracrine way to support the endothelium (51).…”

“…Radiation-induced damage to the vasculature will cause secondary damage to the tissue. Because G-CSF alone or in combination with Flt-3L or SCF has been shown to promote the formation of blood vessels after myocardial infarct (27), the vascular structure of irradiated glands was investigated. Microscopic comparison of the vasculature of glands of all groups, visualized by CD31 staining, immediately indicated differences in blood vessel morphology at 90 days post-IR.…”

Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial

“…Interestingly, positive data from animal studies used protocols with G-CSF administration before or at the time of infarct. [21][22][23][24] By comparison, in a study of immediate versus delayed (5 d postinfarct) G-CSF therapy, delayed therapy was associated with a 24% increase in end diastolic volume and a significant increase in infarct mass relative to placebo. 12 Similarly, a previous meta-analysis of clinical studies suggested benefit with early (< 37 h) initiation of G-CSF therapy.…”