Abstract
ObjectiveEndothelial-colony forming cells (ECFCs) can be readily expanded from human umbilical cord blood and can facilitate repair of endothelial injury. E-selectin and SDF-1α are produced following endothelial injury and can regulate endothelial progenitor homing. Mechanisms of vascular repair specific to the mode of injury have not been well described in homogenous cell populations such as ECFCs and are needed for development of more effective vascular repair strategies.Methods and ResultsLipopolysaccharide (LPS)-induced endotoxic injury to mature human umbilical vein endothelial cells (HUVEC) was compared with hypoxic and radiation injury. E-selectin expression in HUVEC cells is markedly increased (208-fold) following LPS-induced injury and facilitates increased ECFC adhesion and migration function in vitro. SDF-1α expression remains unchanged in LPS-treated HUVEC cells but increases more than 2 fold in fibroblasts undergoing similar endotoxic injury. SDF-1α induces expression of E-selectin ligands on ECFCs and facilitates greater E-selectin-mediated adhesion and migration of ECFCs in a CXCR4-dependent manner. Induction of E-selectin expression in HUVECs following hypoxic or radiation injury is negligible, however, while SDF-1α is increased markedly following hypoxia, highlighting injury-specific synergism between mediators of vascular repair.ConclusionE-selectin mediates adhesion and migration of ECFCs following endotoxic endothelial injury. SDF-1α augments E-selectin mediated ECFC adhesion and migration in a CXCR4-dependent manner.
Highlights
Vascular endothelial injury underlies many medical conditions including sepsis, occlusive vascular disease affecting the renal, cardiovascular and cerebrovascular systems, microangiopathies such as thrombotic thrombocytopenic purpura, vasculitic disorders including autoimmune conditions, and graft versus host disease that can complicate blood stem cell transplantation
Since Asahara et al [1] first described endothelial progenitor cells (EPCs) as a subset of CD34+ cells isolated from bone marrow, endothelial progenitors and related cell types have been characterized from bone marrow, peripheral blood, or other tissues and contribute to endothelial repair and neovascularization in several models of endothelial damage [2]
Expression of key genes associated with endothelial injury was performed following LPS treatment of human umbilical vein endothelial cells (HUVEC) cells and included assessment of E-selectin, VCAM-1, ICAM-1 and SDF-1a
Summary
Vascular endothelial injury underlies many medical conditions including sepsis, occlusive vascular disease affecting the renal, cardiovascular and cerebrovascular systems, microangiopathies such as thrombotic thrombocytopenic purpura, vasculitic disorders including autoimmune conditions, and graft versus host disease that can complicate blood stem cell transplantation. Vascular injury can be systemic or isolated to a single organ and may be caused by various insults including ischemia, endotoxic damage related to infection, immune-mediated or following treatments such as chemotherapy and radiation. Since Asahara et al [1] first described endothelial progenitor cells (EPCs) as a subset of CD34+ cells isolated from bone marrow, endothelial progenitors and related cell types have been characterized from bone marrow, peripheral blood, or other tissues and contribute to endothelial repair and neovascularization in several models of endothelial damage [2]. Circulating endothelial progenitors represent a heterogeneous population of myeloid and monocytic cells derived from bone marrow and may include rare cells with specific endothelial precursor function.[3,4] Early outgrowth EPCs are a heterogenous population of adherent mononuclear cells from peripheral blood or umbilical cord blood that emerges in vitro under angiogenic culture conditions after approximately 5 – 7 days.[5] The precise identity of various endothelial progenitor cell populations remains under active study. Ex vivo expansion of endothelial colony forming cells (ECFCs) from peripheral blood or umbilical cord blood provides a homogenous population of endothelial-like cells with a high proliferative capacity, blood-forming function and therapeutic potential in several models of vascular injury. [5,6,7] cells that contribute to vascular repair can be differentiated from
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