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(Circulation. 2006;114:I-94 – I-100.)
© 2006 American Heart Association, Inc.

Cell Transplantation and Tissue Engineering

Ex Vivo Activated Human Macrophages Improve Healing, Remodeling, and Function of the Infarcted Heart

Jonathan Leor, MD; Liat Rozen, MSc; Adi Zuloff-Shani, PhD; Micha S. Feinberg, MD; Yoram Amsalem, MD; Israel M. Barbash, MD; Erez Kachel, MD; Radka Holbova; Yael Mardor, PhD; Dianne Daniels, MSc; Aharon Ocherashvilli, PhD; Arie Orenstein, MD; David Danon, MD

From Neufeld Cardiac Research Institute (J.L., L.R., M.S.F., Y.A., I.M.B., R.H.), Tel-Aviv University; Research and Development Unit (A.Z.S., D.D.), Blood Service Center, Magen David Adom; Department of Cardiac and Thoracic Surgery (E.K.); The Advanced Technology Center (Y.M., D.D., A.O., A.Orenstein), Sheba Medical Center, Tel-Hashomer, Israel.

Correspondence to Jonathan Leor, Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail Hleorj{at}post.tau.ac.il

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.

Methods and 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 (&4x10⁵ 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.

Key Words: immune system • inflammation • myocardial infarction • remodeling • magnetic resonance imaging

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