Myocardial homing and neovascularization by human bone marrow angioblasts is regulated by IL-8/Gro CXC chemokines

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.

Introduction

Healing of a myocardial infarct is complicated by the need for viable myocytes at the peri-infarct rim to undergo compensatory hypertrophy in order to increase pump function in response to the loss of infarcted tissue [1], [2]. This initiates a process termed cardiac remodeling, characterized by apoptotic loss of hypertrophied myocytes, expansion of the initial infarct area, progressive collagen replacement, and heart failure [3], [4], [5], [6]. We have recently demonstrated that apoptosis of hypertrophied cardiomyocytes occurs, in part, because the endogenous capillary 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 between endothelial cells in pre-existing vasculature and extracellular matrix which are regulated by locally-produced factors and which lead to endothelial cell migration, proliferation, reorganization and microvessel formation [8]. Among these factors 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 human ventral aorta which give rise to both endothelial and haematopoietic elements [13], [14], [15], [16]. Cells which can differentiate into endothelial elements have been shown to also be present in adult bone marrow [17], [18], [19] and to be able to induce vasculogenesis in post-natal ischemic tissues [20], [21], [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]. Hypothesizing that the inadequate angiogenic response post-myocardial infarction was due to a lack of angioblasts present locally at the infarct zone, we administered these cells intravenously and observed homing to ischemic myocardium, induction of infarct bed vasculogenesis, prevention of peri-infarct myocyte apoptosis, and significant improvement in myocardial function.

A number of signaling factors, including cytokines, chemokines and growth factors, which are involved in orchestrating the process of mobilization, homing, incorporation, survival, proliferation and differentiation of stem cells, that leads to myocardial regeneration have only recently been recognized [23], [24]. Understanding interactions of the signals from the ischemic myocardium required for chemoattraction of bone marrow-derived endothelial precursors, and the receptors used by these cells for selective trafficking to these sites, is critical in designing new strategies for enhancement of repair. In the present study we investigated whether CXC chemokines containing the ELR motif regulate migration of human bone marrow-derived angioblasts to sites of tissue ischemia.