Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart.
BACKGROUND
Activated macrophages have a significant role in wound healing and damaged tissue repair. We sought to explore the ability of ex vivo activated macrophages to promote healing and repair of the infarcted myocardium.


RESULTS
Human activated macrophage suspension (AMS) was prepared from a whole blood unit obtained from young donors in a closed sterile system and was activated by a novel method of hypo-osmotic shock. The AMS (approximately 4 x 10(5) cells) included up to 43% CD14-positive cells and was injected into the ischemic myocardium of rats (n=8) immediately after coronary artery ligation. The control group (n=9) was treated with saline injection. The human cells existed in the infarcted heart 4 to 7 days after injection, as indicated by histology, human growth hormone-specific polymerase chain reaction, and magnetic resonance imaging (MRI) tracking of iron oxide-nanoparticle-labeled cells. After 5 weeks, scar vessel density (+/-SE) (25+/-4 versus 10+/-1 per mm2; P<0.05), myofibroblast accumulation, and recruitment of resident monocytes and macrophages were greater in AMS-treated hearts compared with controls. Serial echocardiography studies, before and 5 weeks after injection, showed that AMS improved scar thickening (0.15+/-0.01 versus 0.11+/-0.01 cm; P<0.05), reduced left ventricular (LV) diastolic dilatation (0.87+/-0.02 versus 0.99+/-0.04 cm; P<0.05), and improved LV fractional shortening (31+/-2 versus 20+/-4%; P<0.05), compared with controls.


CONCLUSIONS
Early after myocardial infarction, injection of AMS accelerates vascularization, tissue repair, and improves cardiac remodeling and function. Our work suggests a novel clinically relevant option to promote the repair of ischemic tissue.
Leor
Jonathan
J
Neufeld Cardiac Research Institute, Tel-Aviv University, Israel. Hleorj@post.tau.ac.il
Rozen
Liat
L
Zuloff-Shani
Adi
A
Feinberg
Micha S
MS
Amsalem
Yoram
Y
Barbash
Israel M
IM
Kachel
Erez
E
Holbova
Radka
R
Mardor
Yael
Y
Daniels
Dianne
D
Ocherashvilli
Aharon
A
Orenstein
Arie
A
Danon
David
D
D000293:Adolescent; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002921:Cicatrix / Q000473:pathology; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D019382:Human Growth Hormone / Q000032:analysis; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000737:chemistry / Q000502:physiology / Q000637:transplantation*; D008279:Magnetic Resonance Imaging; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000601:surgery*; D018919:Neovascularization, Physiologic; D009997:Osmotic Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D014945:Wound Healing; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D006684:HLA-DR Antigens; D019382:Human Growth Hormone; C067980:CD68 antigen, human; D000097382:CD68 Molecule