Postinfarct cytokine therapy regenerates cardiac tissue and improves left ventricular function.
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)+Flt-3 ligand (FL), G-CSF+stem 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-CSF+FL- and G-CSF+SCF-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-CSF+FL or G-CSF+SCF, but the numbers were much smaller in G-CSF-treated mice. G-CSF+FL 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-CSF+FL or G-CSF+SCF 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.
Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
Buddhadeb
B
Dawn
Yiru
Y
Guo
Arash
A
Rezazadeh
Yiming
Y
Huang
Adam B
AB
Stein
Greg
G
Hunt
Sumit
S
Tiwari
Jai
J
Varma
Yan
Y
Gu
Sumanth D
SD
Prabhu
Jan
J
Kajstura
Piero
P
Anversa
Suzanne T
ST
Ildstad
Roberto
R
Bolli
D000818:Animals; D002455:Cell Division; D016207:Cytokines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D017930:Genes, Reporter; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D012038:Regeneration / Q000187:drug effects; D019089:Stem Cell Factor / Q000627:therapeutic use; D014463:Ultrasonography; D016276:Ventricular Function; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
D016207:Cytokines; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins