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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1653.)
© 2006 American Heart Association, Inc.

Thrombosis

Fibrin and Activated Platelets Cooperatively Guide Stem Cells to a Vascular Injury and Promote Differentiation Towards an Endothelial Cell Phenotype

H.C. de Boer; C. Verseyden; L.H. Ulfman; J.J. Zwaginga; I. Bot; E.A. Biessen; T.J. Rabelink; A.J. van Zonneveld

From the Department of Nephrology (H.C.d.B., C.V., T.J.R., A.J.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Department of Pulmonary Diseases (L.H.U.), University Medical Center Utrecht, The Netherlands; Departments of Experimental Immunohaematology and Immunohaematology-Bloodtransfusion (J.J.Z.), Sanquin Research, Amsterdam and Leiden University Medical Center, Leiden, The Netherlands; Division of Biopharmaceutics (I.B., E.A.B.), Leiden/Amsterdam Center for Drug Research, Gorleaus Laboratories, Leiden University, The Netherlands.

Correspondence to Dr Hetty C. de Boer, Department of Nephrology, C3P25, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail h.c.deboer{at}lumc.nl

Objective— Bone marrow-derived progenitor cells play a role in vascular regeneration. However, their homing to areas of vascular injury is poorly understood. One of the earliest responses to an injury is the activation of coagulation and platelets. In this study we assessed the role of hemostatic components in the recruitment of CD34⁺ cells to sites of injury.

Methods and Results— Using an ex vivo injury model, representing endothelial cell (EC) injury or vessel denudation, we studied homing of CD34⁺ under flow. Platelet aggregates facilitated initial tethering and rolling of CD34⁺ cells through interaction of P-selectin expressed by platelets and P-selectin glycoprotein ligand-1 (PSGL-1), expressed by CD34⁺ cells. Ligation of PSGL-1 activated adhesion molecules on CD34⁺ cells, ultimately leading to firm adhesion of CD34⁺ cells to tissue factor-expressing ECs or to fibrin-containing thrombi formed on subendothelium. We also demonstrate that fibrin-containing thrombi can support migration of CD34⁺ cells to the site of injury and subsequent differentiation toward a mature EC phenotype. Additionally, intravenously injected CD34⁺ cells homed in vivo to denuded arteries in the presence of endogenous leukocytes.

Conclusions— We provide evidence that hemostatic factors, associated with vascular injury, provide a regulatory microenvironment for re-endothelialization mediated by circulating progenitor cells.

The hemostatic factors fibrin and activated platelets cooperatively provide the local cues for CD34⁺ cells to escape (tether and roll) from flowing blood, migrate towards an injury, and differentiate into a more mature endothelial phenotype, ultimately leading to repair of a vascular injury.

Key Words: platelets • coagulation • fibrinogen/fibrin • aggregation • other vascular biology

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