Journal article
Platelets regulate lymphatic vascular development through CLEC-2–SLP-76 signaling
- Bertozzi, Cara C. Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Schmaier, Alec A. Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Mericko, Patricia Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Hess, Paul R. Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Zou, Zhiying Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Chen, Mei Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Chen, Chiu-Yu Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Xu, Bin Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Lu, Min-min Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Zhou, Diane Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
- Sebzda, Eric Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN;
- Santore, Matthew T. Department of Surgery, Children's Hospital of Philadelphia, PA;
- Merianos, Demetri J. Department of Surgery, Children's Hospital of Philadelphia, PA;
- Stadtfeld, Matthias Harvard Stem Cell Institute, Boston, MA;
- Flake, Alan W. Department of Surgery, Children's Hospital of Philadelphia, PA;
- Graf, Thomas Center for Genomic Regulation (CRG), Barcelona, Spain;
- Skoda, Radek Department of Research, University Hospital Basel, Basel, Switzerland; and
- Maltzman, Jonathan S. Department of Medicine and
- Koretzky, Gary A. Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia
- Kahn, Mark L. Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia;
Published in:
- Blood. - American Society of Hematology. - 2010, vol. 116, no. 4, p. 661-670
English
Abstract
Although platelets appear by embryonic day 10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK–SLP-76 signaling pathway is required in blood cells to regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. Platelet factor 4-Cre–mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76–dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1182/blood-2010-02-270876
- ISSN 0006-4971
- Persistent URL
- https://folia.unifr.ch/global/documents/125013
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