Original article Myocardial homing and neovascularization by human bone marrow angioblasts is regulated by IL-8/Gro CXC chemokines A.A. Kocher a,* , M.D. Schuster a , N. Bonaros a , K. Lietz a , G. Xiang a , T.P. Martens a , P.A. Kurlansky b , H. Sondermeijer a , P. Witkowski a , A. Boyle a , S. Homma a , S.F. Wang a , S. Itescu a a Department of Surgery, Medicine, and Pathology, Columbia University, New York b Department of Surgery, Medicine, and Pathology, Miami Heart Research Institute, Florida Received 18 July 2005; received in revised form 22 November 2005; accepted 30 November 2005 Available online 24 January 2006 Abstract In the adult, new blood vessel formation can occur either through angiogenesis from pre-existing mature endothelium or vasculogenesis mediated by bone marrow-derived endothelial precursors. We recently isolated endothelial progenitor cells, or angioblasts, in human adult bone marrow which have selective migratory properties for ischemic tissues, including myocardium, to where they home and induce vasculogenesis. Here we show that myocardial production of the IL-8/Gro-alpha CXC chemokine family is significantly increased after acute ischemia, and that this provides a chemoattractant gradient for bone marrow-derived endothelial progenitors, or angioblasts. This chemokine-mediated homing of bone marrow angioblasts to the ischemic heart regulates their ability to induce myocardial neovascularization, protection against cardiomyocyte apoptosis, and functional cardiac recovery. Together, our results indicate that CXC chemokines play a central role in regulating vasculogenesis in the adult, and suggest that manipulation of interactions between chemokines and their receptors on autologous human bone marrow-derived angioblasts could augment neovascularization of ischemic myocardial tissue. © 2006 Elsevier Ltd. All rights reserved. 1. Introduction Healing of a myocardial infarct is complicated by the need for viable myocytes at the peri-infarct rim to undergo compen- satory hypertrophy in order to increase pump function in re- sponse to the loss of infarcted tissue [1,2]. This initiates a pro- cess termed cardiac remodeling, characterized by apoptotic loss of hypertrophied myocytes, expansion of the initial infarct area, progressive collagen replacement, and heart failure [3–6]. We have recently demonstrated that apoptosis of hypertrophied cardiomyocytes occurs, in part, because the endogenous capil- lary network cannot provide a sufficient increase in perfusion required for cell survival [7]. The angiogenic response during wound repair results from changes in adhesive interactions be- tween endothelial cells in pre-existing vasculature and extracel- lular matrix which are regulated by locally-produced factors and which lead to endothelial cell migration, proliferation, re- organization and microvessel formation [8]. Among these fac- tors are the human CXC chemokine family consisting of small (< 10 kDa) heparin-binding polypeptides that bind to and have potent chemotactic activity for endothelial cells. Three amino acid residues at the N-terminus (Glu-Leu-Arg, the ELR motif) determine binding of CXC chemokines such as IL-8 and Gro- alpha to CXC receptors 1 and 2 on endothelial cells [9,10], thus promoting endothelial chemotaxis and angiogenesis [11, 12]. Vascular network formation is the end result of a complex process that begins in the pre-natal period with induction of vasculogenesis by haemangioblasts, cells derived from the hu- man ventral aorta which give rise to both endothelial and hae- matopoietic elements [13–16]. Cells which can differentiate into endothelial elements have been shown to also be present in adult bone marrow [17–19] and to be able to induce vascu- logenesis in post-natal ischemic tissues [20–22]. We recently identified a specific population of endothelial progenitor cells derived from human adult bone marrow with phenotypic and functional characteristics of embryonic angioblasts [7]. Hy- www.elsevier.com/locate/yjmcc Journal of Molecular and Cellular Cardiology 40 (2006) 455–464 * Corresponding author. Medical University Vienna, Cardiothoracic Surgery, Waehringerguertel 18-20, 1090 Vienna, Austria. Tel.: +43 1 40400 5620; fax: +43 1 40400 5640. E-mail address: Alfred.Kocher@meduniwien.ac.at (A.A. Kocher). 0022-2828/$ - see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2005.11.013