Endothelial Protein C Receptor (CD201) Explicitly Identifies Hematopoietic Stem Cells in Murine Bone Marrow

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2005 Nov 24

PMID 16304059

Citations 146

Authors

Alejandro B Balazs

Attila J Fabian

Charles T Esmon

Richard C Mulligan

Affiliations

Soon will be listed here.

Abstract

The hematopoietic stem cell (HSC) is a unique cell type found in bone marrow, which has the capacity for both self-renewal and differentiation into all blood lineages. The identification of genes expressed specifically in HSCs may help identify gene products vital to the control of self-renewal and/or differentiation, as well as antigens capable of forming the basis for improved methods of stem cell isolation. In previous studies, we identified a number of genes that appeared to be differentially expressed in murine bone marrow-derived HSCs, using microarray technology. We report here that one of those genes, encoding the murine endothelial protein C receptor (EPCR), is expressed at high levels within the bone marrow in HSCs. Bone marrow cells isolated on the basis of EPCR expression alone are highly enriched for hematopoietic reconstitution activity, showing levels of engraftment in vivo comparable to that of stem cells purified using the most effective conventional methods. Moreover, evaluation of cell populations first enriched for stem cell activity by conventional methods and subsequently fractionated on the basis of EPCR expression indicates that stem cell activity is always associated with EPCR-expressing cells. Based on our findings, we believe EPCR represents the first known marker that 'explicitly' identifies hematopoietic stem cells within murine bone marrow.

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References

Matsuzaki Y, Kinjo K, Mulligan R, Okano H . Unexpectedly efficient homing capacity of purified murine hematopoietic stem cells. Immunity. 2004; 20(1):87-93. DOI: 10.1016/s1074-7613(03)00354-6. View

Chen C, Li M, de Graaf D, Monti S, Gottgens B, Sanchez M . Identification of endoglin as a functional marker that defines long-term repopulating hematopoietic stem cells. Proc Natl Acad Sci U S A. 2002; 99(24):15468-73. PMC: 137740. DOI: 10.1073/pnas.202614899. View

Harrison D . Competitive repopulation: a new assay for long-term stem cell functional capacity. Blood. 1980; 55(1):77-81. View

Berman J, BASCH R . Thy-1 antigen expression by murine hematopoietic precursor cells. Exp Hematol. 1985; 13(11):1152-6. View

Spangrude G, Klein J, Heimfeld S, Aihara Y, Weissman I . Two monoclonal antibodies identify thymic-repopulating cells in mouse bone marrow. J Immunol. 1989; 142(2):425-30. View

Pages G, Lenormand P, LAllemain G, Chambard J, Meloche S, Pouyssegur J . Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A. 1993; 90(18):8319-23. PMC: 47347. DOI: 10.1073/pnas.90.18.8319. View

Fukudome K, Esmon C . Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). The structural and functional conservation in human, bovine, and murine EPCR. J Biol Chem. 1995; 270(10):5571-7. DOI: 10.1074/jbc.270.10.5571. View

Morrison S, Uchida N, Weissman I . The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol. 1995; 11:35-71. DOI: 10.1146/annurev.cb.11.110195.000343. View

Goodell M, Brose K, Paradis G, Conner A, Mulligan R . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996; 183(4):1797-806. PMC: 2192511. DOI: 10.1084/jem.183.4.1797. View

10.

Osawa M, Hanada K, Hamada H, Nakauchi H . Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996; 273(5272):242-5. DOI: 10.1126/science.273.5272.242. View

11.

Ludeman M, Kataoka H, Srinivasan Y, Esmon N, Esmon C, Coughlin S . PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem. 2005; 280(13):13122-8. DOI: 10.1074/jbc.M410381200. View

12.

Kiel M, Yilmaz O, Iwashita T, Yilmaz O, Terhorst C, Morrison S . SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005; 121(7):1109-21. DOI: 10.1016/j.cell.2005.05.026. View

13.

Li W, Zheng X, Gu J, Ferrell G, Brady M, Esmon N . Extraembryonic expression of EPCR is essential for embryonic viability. Blood. 2005; 106(8):2716-22. PMC: 1895308. DOI: 10.1182/blood-2005-01-0406. View

14.

Muller-Sieburg C, Whitlock C, Weissman I . Isolation of two early B lymphocyte progenitors from mouse marrow: a committed pre-pre-B cell and a clonogenic Thy-1-lo hematopoietic stem cell. Cell. 1986; 44(4):653-62. DOI: 10.1016/0092-8674(86)90274-6. View

15.

Esmon C . The endothelial cell protein C receptor. Thromb Haemost. 2000; 83(5):639-43. View

16.

Coughlin S . Thrombin signalling and protease-activated receptors. Nature. 2000; 407(6801):258-64. DOI: 10.1038/35025229. View

17.

Tsuneyoshi N, Fukudome K, Horiguchi S, Ye X, Matsuzaki M, Toi M . Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thromb Haemost. 2001; 85(2):356-61. View

18.

Galligan L, Livingstone W, Volkov Y, Hokamp K, Murphy C, Lawler M . Characterization of protein C receptor expression in monocytes. Br J Haematol. 2001; 115(2):408-14. DOI: 10.1046/j.1365-2141.2001.03187.x. View

19.

Christensen J, Weissman I . Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A. 2001; 98(25):14541-6. PMC: 64718. DOI: 10.1073/pnas.261562798. View

20.

Riewald M, Petrovan R, Donner A, Mueller B, Ruf W . Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002; 296(5574):1880-2. DOI: 10.1126/science.1071699. View