6-Integrin Subunit Plays a Major Role in the Proangiogenic Properties of Endothelial Progenitor Cells (original) (raw)
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Arteriosclerosis, Thrombosis, and Vascular Biology, 2010
Objective-Alpha6 integrin subunit (␣6) expression is increased by proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor. This increase correlates with enhanced in vitro tube formation by endothelial cells and their progenitors called Endothelial Colony-Forming Cells (ECFCs). We thus studied the role of ␣6 in vasculogenesis induced by human ECFCs, in a mouse model of hindlimb ischemia. Methods and Results-We used small interfering RNA (siRNA) to inhibit ␣6 expression on the surface of ECFCs. For in vivo studies, human ECFCs were injected intravenously into a nude mouse model of unilateral hind limb ischemia. Transfection with siRNA ␣6 abrogated neovessel formation and reperfusion of the ischemic hind limb induced by ECFCs (PϽ0.01 and PϽ0.001, respectively). It also inhibited ECFC incorporation into the vasculature of the ischemic muscle (PϽ0.001). In vitro, siRNA ␣6 inhibited ECFC adhesion (PϽ0.01), pseudotube formation on Matrigel, migration, and AKT phosphorylation (PϽ0.0001), with no effect on cell proliferation or apoptosis. Conclusion-␣6 Expression is required for ECFC migration, adhesion, recruitment at the site of ischemia, and the promotion of the postischemic vascular repair. Thus, we have demonstrated a major role of ␣6 in the proangiogenic properties of ECFCs.
Integrin Subunit Plays a Major Role in the Proangiogenic Properties of Endothelial Progenitor Cells
2010
Objective-Alpha6 integrin subunit (␣6) expression is increased by proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor. This increase correlates with enhanced in vitro tube formation by endothelial cells and their progenitors called Endothelial Colony-Forming Cells (ECFCs). We thus studied the role of ␣6 in vasculogenesis induced by human ECFCs, in a mouse model of hindlimb ischemia. Methods and Results-We used small interfering RNA (siRNA) to inhibit ␣6 expression on the surface of ECFCs. For in vivo studies, human ECFCs were injected intravenously into a nude mouse model of unilateral hind limb ischemia. Transfection with siRNA ␣6 abrogated neovessel formation and reperfusion of the ischemic hind limb induced by ECFCs (PϽ0.01 and PϽ0.001, respectively). It also inhibited ECFC incorporation into the vasculature of the ischemic muscle (PϽ0.001). In vitro, siRNA ␣6 inhibited ECFC adhesion (PϽ0.01), pseudotube formation on Matrigel, migration, and AKT phosphorylation (PϽ0.0001), with no effect on cell proliferation or apoptosis. Conclusion-␣6 Expression is required for ECFC migration, adhesion, recruitment at the site of ischemia, and the promotion of the postischemic vascular repair. Thus, we have demonstrated a major role of ␣6 in the proangiogenic properties of ECFCs.
Circulation Research, 1999
Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing -galactosidase under the transcriptional regulation of an endothelial cell-specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1-or Tie-2expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.
Endothelial progenitor cells: identity defined?
Journal of Cellular and Molecular Medicine, 2008
In the past decade, researchers have gained important insights on the role of bone marrow (BM)-derived cells in adult neovascularization. A subset of BM-derived cells, called endothelial progenitor cells (EPCs), has been of particular interest, as these cells were suggested to home to sites of neovascularization and neoendothelialization and differentiate into endothelial cells (ECs) in situ, a process referred to as postnatal vasculogenesis. Therefore, EPCs were proposed as a potential regenerative tool for treating human vascular disease and a possible target to restrict vessel growth in tumour pathology. However, conflicting results have been reported in the field, and the identification, characterization, and exact role of EPCs in vascular biology is still a subject of much discussion. The focus of this review is on the controversial issues in the field of EPCs which are related to the lack of a unique EPC marker, identification challenges related to the paucity of EPCs in the circulation, and the important phenotypical and functional overlap between EPCs, haematopoietic cells and mature ECs. We also discuss our recent findings on the origin of endothelial outgrowth cells (EOCs), showing that this in vitro defined EC population does not originate from circulating CD133 ϩ cells or CD45 ϩ haematopoietic cells. Dimmeler S, Zeiher AM. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.
Endothelial progenitor cells and integrins: adhesive needs
Fibrogenesis & Tissue Repair, 2012
In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent.
Role of 2-integrins for homing and neovascularization capacity of endothelial progenitor cells
Journal of Experimental Medicine, 2005
The mechanisms of homing of endothelial progenitor cells (EPCs) to sites of ischemia are unclear. Here, we demonstrate that ex vivo-expanded EPCs as well as murine hematopoietic Sca-1 ϩ /Lin Ϫ progenitor cells express  2-integrins, which mediate the adhesion of EPCs to endothelial cell monolayers and their chemokine-induced transendothelial migration in vitro. In a murine model of hind limb ischemia, Sca-1 ϩ /Lin Ϫ hematopoietic progenitor cells from  2-integrin-deficient mice are less capable of homing to sites of ischemia and of improving neovascularization. Preactivation of the  2-integrins expressed on EPCs by activating antibodies augments the EPC-induced neovascularization in vivo. These results provide evidence for a novel function of  2-integrins in postnatal vasculogenesis.
Advances in wound care, 2013
Postnatal vasculogenesis mediated via endothelial progenitor cells (EPCs) contributes to re-endothelialization and augments neovascularization after ischemia and tissue injury, providing a novel therapeutic application. However, controversy exists with respect to the origin, identification, and contributions of the EPCs to neovascularization, necessitating further study. Bone marrow (BM) or circulating cells expressing cd133/vascular endothelial growth factor receptor 2 include those with endothelial progenitor capacity. Increasing evidence suggests that there are additional BM-derived (myeloid; mesenchymal cells) and non-BM-derived (peripheral and cord-blood; tissue-resident) cell populations which also give rise to endothelial cells (ECs) and contribute to re-endothelialization and growth factor release after ischemia and tissue injury. Currently, EPCs are being used as diagnostic markers for the assessment of cardiovascular and tumor risk/progression. Techniques aimed at enhancin...
Endothelial progenitor cells: Quo Vadis?
Journal of Molecular and Cellular Cardiology, 2011
The term endothelial progenitor cell (EPC) was coined to refer to circulating cells that displayed the ability to display cell surface antigens similar to endothelial cells in vitro, to circulate and lodge in areas of ischemia or vascular injury, and to facilitate the repair of damaged blood vessels or augment development of new vessels as needed by a tissue. More than 10 years after the first report, the term EPC is used to refer to a host of circulating cells that display some or all of the qualities indicated above, however, essentially all of the cells are now known to be members of the hematopoietic lineage. The exception is a rare viable circulating endothelial cell with clonal proliferative potential that displays the ability to spontaneously form inosculating human blood vessels upon implantation into immunodeficient murine host tissues. This paper will review the current lineage relationships among all the cells called EPC and will propose that the term EPC be retired and that each of the circulating cell subsets be referred to according to the terms already existent for each subset. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".